Non-invasive dynamic measurement of intracranial reserve space

ABSTRACT

System for non-invasive measuring of an intracranial reserve space (ICRS) parameter of a mammalian subject, comprising a multi-frequency ultrasound probe configured, beginning at a start time, to emit and receive ultrasound waves into and from the subject&#39;s head and to produce a signal of brain tissue pulsation; an instrument configured to non-invasively partially occlude an internal jugular vein (IJV) starting at the start time and including a second ultrasound probe producing a second signal; and a computer system configured to receive the signal, the second signal and the start time, the computer system also configured, using one or more processors, to derive from the signal an intracranial brain tissue pulsation waveform and from the second signal images of the IJV, and to determine a length of time from the start time to a subsequent time at which the waveform is sufficiently compressed so as to exhibit a predefined decline in variability.

FIELD AND BACKGROUND OF THE INVENTION

The present invention is in the field of medical diagnostic devices andmethods. More particularly, the present invention aims to dynamicallymeasure the intracranial reserve space noninvasively.

From the instant a patient with suspected brain injury arrives at theemergency room, a wide variety of complicated tests are obtained to helpdetermine this damage. Clinical neurological investigations can bebroadly classified in two ways: those that examine the anatomy of thebrain (CAT scan and MRI) and those that examine the function of thebrain (EEG, SPECT, and PET scan). Some of these are time-consuming andimpractical for dynamic investigation such as repeating tests hourly ordaily. While these diagnostic tools have advanced the understanding ofthe broad ranges of normative brain function, they disadvantageouslyrely on complex, expensive equipment that cannot be used continuouslyand near the bedside, and are available only in focal hospitals and notin peripheral medical clinics.

A CT scan, for instance, cannot be performed on a patient over and overwithin a period of 24 hours, or in some cases 6 hours, to determineanatomical deterioration in the brain, without subjecting the patient todangerously mutagenic levels of radiation. It is also impractical todevote an expensive CT apparatus to repeated use on a single patient.

The “gold standard” to date for non-invasive measurement of the IntraCranial Reserve Space (ICRS) is MRI Voxel Volumetry (MRIVV). However,MRIVV is expensive to purchase and to operate. It is also time consumingas the MRI scan is marked by hand, and cannot be used for wide clinicalpractices. It cannot be used repeatedly within a brief time frame suchas minutes, hours, days or even a month, and cannot be used bedside.Interpretation of the results of the MRIVV usually requires aneuroradiologist to be present.

The need exists for an apparatus, preferably a portable bedsideapparatus, that could be used repeatedly, for example within minutes orhours or days or months, and noninvasively on patients under observationfor a suspected head injury or other neurological or neurosurgicalcondition, for example in order to ascertain whether anatomicaldeterioration has occurred over time.

SUMMARY OF THE INVENTION

One aspect of the present invention is a system for non-invasivemonitoring of an intracranial reserve space (ICRS) parameter of amammalian subject, comprising a multi-frequency at least two-dimensionalultrasound probe configured, beginning at a start time, to emit andreceive ultrasound waves into and from a head of the subject and toproduce a signal of intracranial brain tissue pulsations in at least ahorizontal spatial and a vertical spatial dimension, the brain tissuepulsations responsive to pulses of a heart systole and/or arterialpressure; an instrument configured to non-invasively apply a pressure toeffectuate a partial occlusion of an internal jugular vein of thesubject, the partial occlusion starting at the start time, theinstrument including a second ultrasound probe configured to produce asecond signal for imaging the internal jugular vein; and a computersystem configured to receive the signal and an output of the start timeof the partial occlusion of the internal jugular vein of the subject,the computer system also configured, using one or more processors, toderive from the signal of intracranial brain tissue pulsations anintracranial brain tissue pulsation waveform based on at leastthree-dimensional pulsatility of the intracranial brain tissue, and todetermine a length of time from the start time to a subsequent time atwhich the waveform is sufficiently compressed so as to exhibit apredefined decline in variability of at least 10%, the computer systemalso configured to receive the second signal and to derive from thesecond signal images of the internal jugular vein.

In some embodiments, the multi-frequency ultrasound probe emits intransmission mode at an emitter frequency and the probe receives at areceiver frequency such that the emitter frequency is lower than thereceiver frequency.

In some embodiments, the instrument is configured to measure thepressure and wherein the instrument is configured to apply an initialpressure and subsequent greater pressures in uniform increments to theinternal jugular vein.

In some embodiments, the instrument includes a motor or a compressor, atleast one piston movable within a housing, and an applicator thatincludes the second ultrasound probe, a distal end of the applicatorshaped to engage the neck of the subject.

In some embodiments, the multi-frequency ultrasound probe has apiezoelectric array configured to adapt to a shape of the skull.

In some embodiments, the multi-frequency ultrasound probe emits at afrequency of 0.5 to 3 MHz and receives at a frequency of 1.0 MHz to 6.0MHz.

In some embodiments, an end of the multi-frequency ultrasound probe isshaped to conform to a skull and wherein the ultrasound probe emits at afrequency of about 1.0 MHz and receives at a frequency of up to 1.76 MHzusing a carrier frequency of about 0.5 MHz to 1.76 MHz.

In some embodiments, variability of the waveform comprises at least oneof the following parameters: (i) a variability of an amplitude of thewaveform, (ii) a variability of an area under the curve of the waveform,(iii) a variability of a dominant frequency of the waveform (iv) adirection of high frequency shift of the waveform, (v) a phase shift ofthe waveform and (vi) a variability of a multiaxial spectroscopy of thewaveform.

In some embodiments, the computer system is further configured toconvert the signal into a dynamic image of a multiaxial pulsatility ofbrain tissue in at least a part of the head that the probe receivedultrasound waves from.

In some embodiments, the computer system is configured to determine asuspicion that clinical deterioration of the subject is predicted tooccur.

In some embodiments, the computer system is configured to predict atleast one of (i) an elevated ICP of the subject and (ii) clinicaldeterioration of the subject, the prediction being derived from thedetermination of an intracranial reserve space (ICRS) parameter, whereinthe ICRS parameter is at least one of (i) the length of time (T) and(ii) the intracranial reserve space (ICRS) capacity.

In some embodiments, the computer system is further configured todetermine a magnitude of an intracranial reserve space (ICRS) parameterduring the length of time (T).

In some embodiments, the computer system is configured to determine amagnitude of an ICRS capacity based on a volume velocity (V) of blockedvenous blood output occluded at the IJV multiplied by the length of time(T).

In some embodiments, the computer system is configured to send an alertpredicting at least one of (i) an elevated intracranial pressure and(ii) clinical deterioration of the subject.

In some embodiments, the computer system is configured to send an alertbased on at least one of the length of time (T) and an intracranialreserve space capacity.

In some embodiments, the alert determines if the length of time iswithin a range of two to three seconds for a given pressure.

In some embodiments, the multi-frequency ultrasound probe is configuredto receive ultrasound waves from at least two different intracraniallocations.

In some embodiments, the two different intracranial locations aredissimilar according to predetermined criteria.

In some embodiments, the computer system is configured to determine arepresentative ICRS parameter from separate respective ICRS magnitudesat the at least two different intracranial locations.

In some embodiments, one or more processors of the computer system areconfigured to determine an ICRS parameter from a relationship of ΔV/ΔP.

In some embodiments, one or more processors of the computer system areconfigured to determine a suspicion that clinical deterioration eitheroccurred or is predicted.

In some embodiments, the intracranial brain tissue pulsation waveform isprovided by the computer system at a resolution of at least 6000 pointsper cycle.

In some embodiments, the computer system is also configured to derive across-sectional image of the IJV from the second signal and to determinean extent of partial occlusion of the IJV.

In some embodiments, the multi-frequency ultrasound probe is configuredto operate in both a transmission mode and an impulse mode such that oneof the (i) emitter and (ii) receiver operates in transmission mode andanother of the (i) emitter and (ii) receiver operates in impulse mode.

In some embodiments, the computer system is configured to determine afurther length of time beginning from the time at which the waveform issufficiently compressed so as to exhibit the predefined decline invariability to a normalization time at which the predefined decline invariability has been reversed, the reversal such that a variability ofthe waveform at the normalization time equals, within a predefineddegree of accuracy, a variability of the waveform at the start time. Insome embodiments, the computer system is configured to send an alertpredicting future clinical deterioration of the subject if the furtherlength of time is excessive or too short relative an expected normalfurther length of time.

In some embodiments, the system further comprises a display forming partof or connected to the computer system, the display configured todynamically display the intracranial pressure waveform so as to visuallydepict the variability of said waveform.

In some embodiments, the multi-frequency ultrasound probe, the secondultrasound probe and the one or more processors work synchronously.

Another aspect of the present invention is a method of non-invasivelymonitoring an intracranial reserve space (ICRS) parameter of a mammaliansubject, comprising using an at least two-dimensional multi-frequencyultrasound probe, emitting and receiving ultrasound waves into and froma head of a subject so as to produce a signal of intracranial braintissue pulsations of the subject during a time interval in at least ahorizontal spatial and a vertical spatial dimension, the brain tissuepulsations responsive to pulses of a heart systole and/or arterialpressure; using an instrument, non-invasively applying a pressure to aneck of the subject to effectuate a partial occlusion of an internaljugular vein of the subject, the partial occlusion starting at a starttime of the time interval, the instrument measuring the pressure andincluding a distal ultrasound probe configured to produce a secondsignal for imaging the internal jugular vein; using a computer system toreceive the signal and derive from the signal an intracranial braintissue pulsation waveform of the subject and the volume velocity of theinternal jugular vein, the computer system also configured to receive anoutput of the start time and to monitor time from the start time, thecomputer system also configured to receive the second signal and toderive from the second signal images of the internal jugular vein; anddetermining, using one or more processors of the computer system, alength of time (T) from the start time to a time when the intracranialbrain tissue pulsation waveform is sufficiently compressed so as toexhibit a predefined decline in variability of at least 10%.

In some embodiments, the method further comprises the multi-frequencyultrasound probe emitting in transmission mode at an emitter frequencyand the probe receiving at a receiver frequency such that the emitterfrequency is lower than the receiver frequency.

In some embodiments, the variability of the waveform comprises at leastone of the following parameters: (i) a variability of an amplitude ofthe waveform and (ii) a variability of an area under the curve of thewaveform, (iii) a variability of a dominant a frequency of the waveform(iv) a direction of high frequency shift of the waveform, (v) a phaseshift of the waveform and (vi) a variability of a multiaxialspectroscopy of the waveform.

In some embodiments, the method further comprises converting the signalinto a dynamic image of a multiaxial pulsatility of brain tissue in asector of the head from which the multi-frequency ultrasound probereceived ultrasound waves.

In some embodiments, the method further comprises having themulti-frequency ultrasound probe emits at between 0.5 and 1.1 MHz andreceives at between 1.0 and 2.2 MHz using a carrier frequency of 0.5 to2.2 MHz.

In some embodiments, the method further comprises applying the pressureby applying an initial pressure and then increasing the pressure fromthe initial pressure stepwise in uniform increments until the predefineddecline in variability of the ICP waveform occurs.

In some embodiments, the method further comprises determining that thesubject has an abnormal intracranial reserve space and that clinicaldeterioration is either predicted to occur or inferred to have occurred.

In some embodiments, the method further comprises determining, using theone or more processors, a magnitude or a relative magnitude of anintracranial reserve space (ICRS) parameter given the pressure appliedfor the length of time (T).

In some embodiments, the method further comprises determining themagnitude of the ICRS parameter using a relationship of a volumevelocity (V) of venous blood output occluded at the internal jugularvein for a given pressure (P) taking into consideration the length oftime (T) of application of the pressure, and wherein the ultrasoundDoppler outputs the linear velocity and cross-sectional diameter of theinternal jugular vein. In some embodiments, the method further comprisesdetermining that a further medical action is needed if the length oftime (T) is less than a predefined length of time for a given pressureapplied to the subject to effectuate the partial occlusion, wherein thepredefined length of time has a specific length that is at least 2seconds and not more than 3 seconds.

In some embodiments, the method further comprises determining anintracranial pressure from the pressure applied to the subject at a timewhen the intracranial brain tissue pulsation waveform begins to declinein variability.

In some embodiments, the method further comprises monitoring the ICRSparameter dynamically.

In some embodiments, the method further comprises applying the pressureto the internal jugular vein for between 3 and 25 seconds so as topartially occlude 5% to 25% of a cross-section of the internal jugularvein.

In some embodiments, the method further comprises applying the pressureto the internal jugular vein for between 3 and 10 seconds so as topartially occlude 5% to 15% of a cross-section of the internal jugularvein.

In some embodiments, the method further comprises repeating the methodat least once so as to determine a subsequent length of time (T), andpredicting at least one of elevated ICP and clinical deterioration, ifthe subsequent length of time (T) is less than the length of time (T) bya predefined amount.

A further aspect of the present invention is a system for non-invasivemonitoring of an intracranial reserve space (ICRS) parameter of amammalian subject, comprising: a multi-frequency ultrasound probeconfigured, beginning at a start time, to emit and receive ultrasoundwaves into and from a head of the subject and to produce a signal ofbrain tissue pulsation; an instrument configured to non-invasively applya pressure to effectuate a partial occlusion of a cross-section of aninternal jugular vein of the subject, the partial occlusion starting atthe start time, the instrument including a second ultrasound probeconfigured to produce a second signal for imaging a cross-section of theinternal jugular vein, the second ultrasound probe having a Dopplerultrasound output for measuring a linear velocity of venous blood at theinternal jugular vein; and a computer system configured to receive thesignal and an output of the start time of the partial occlusion of theinternal jugular vein of the subject, the computer system alsoconfigured to receive the second signal and to derive from the secondsignal an image of the cross-section of the internal jugular vein and todetermine the linear velocity of venous blood at the internal jugularvein, the computer system also configured, using one or more processors,to derive from the signal an intracranial brain tissue pulsationwaveform, and to determine an ICRS capacity from (i) a length of time(T) from the start time to a subsequent time at which the waveform issufficiently compressed so as to exhibit a predefined decline invariability of at least 10% and from (ii) a volume velocity (V) ofblocked venous blood output occluded at the IJV, wherein the volumevelocity is determined by the computer system from the linear velocityof the internal jugular vein derived from the Doppler ultrasound outputand from the image of the cross-section of the internal jugular vein.

These and other features, aspects and advantages of the presentinvention will become better understood with reference to the followingdrawings, descriptions and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments are herein described, by way of example only, withreference to the accompanying drawings, wherein:

FIG. 1A is a vertical side view of an ultrasound probe, in accordancewith one embodiment of the present invention;

FIG. 1B is a perspective view of the ultrasound probe of FIG. 1A, inaccordance with one embodiment of the present invention;

FIG. 1C is a lateral side view of the ultrasound probe of FIG. 1A, inaccordance with one embodiment of the present invention;

FIG. 1Ca is a schematic view of an alternative embodiment for utilizingsprings with piezoelectric crystals for the distal end of an ultrasoundprobe, in accordance with one embodiment of the present invention;

FIG. 2A is a coronal sectional view of a brain MRI and on the right anecho encephalogram showing the real-time pattern of brain pulsation fromultrasound imaging using a one-dimensional A mode ultrasound probe fromwhich it is possible to derive ICP waveform, wherein SSS refers toSuperior Sagittal Sinus, in accordance with one embodiment of thepresent invention;

FIG. 2B is a further sectional view showing in the middle of the figurethe real-time image of multi-dimensional brain tissue pulsation fromtwo-dimensional ultrasound sector imaging and on the left and right ICPwaveform derived from the image, in accordance with one embodiment ofthe present invention;

FIG. 3A is a schematic view of a system for noninvasive ICRS and ICPmonitoring with image guided internal jugular vein (IJV) cross-sectionalcompression and showing nearby the cervical portion of the internalcarotid artery (ICA), in accordance with one embodiment of the presentinvention;

FIG. 3B is a schematic view of one mode of application of probe 20 to asubject's head where the receiver 20B is on the opposite of the headfrom the emitter 20A;

FIG. 3C is a schematic view of a second mode of application of probe 20to a subject's head where receiver 20B is adjacent emitter 20A on thesame side of the head;

FIG. 4 is an anatomy of a cervical axial slice of a subject showing aninternal jugular vein (IJV) and cervical portion of the internal carotidartery (ICA);

FIG. 5 is a Doppler ultrasound image of the internal jugular vein andadjacent internal carotid artery of a subject, used in accordance withone embodiment of the present invention;

FIG. 6 is a perspective view of a pressure application and measuringinstrument and holder, in accordance with one embodiment of the presentinvention;

FIG. 6A is a schematic view of a pressure application and measuringinstrument, in accordance with one embodiment of the present invention;

FIG. 7 is a schematic view of a pressure application instrument, holder,laptop and display and battery charging device and digital manometer, inaccordance with one embodiment of the present invention;

FIG. 8 is a perspective view of a pressure-application andpressure-measuring instrument and holder guided by a 2-dimensionalultrasound image and applicable to a cavity, vessel and tissue of asubject, in accordance with one embodiment of the present invention;

FIG. 9 is a graph of ICP waveform amplitude of a patient from a time inseconds of pressure applied to the IJV until compression of variabilityof ICP waveform, in accordance with one embodiment of the presentinvention;

FIG. 10 is a graph of ICP amplitude of a patient from a time of pressureapplied to the internal jugular vein (IJV) showing compression ofvariability of ICP waveform and until natural recovery of amplitudevariability (vascular cross filling time—VCFT) by means of the IJV onthe opposite side of the neck of the patient, in accordance with oneembodiment of the present invention; and

FIG. 11 is a flow chart showing a method of the present invention inaccordance with one embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description is of the best currently contemplatedmodes of carrying out the invention. The description is not to be takenin a limiting sense, but is made merely for the purpose of illustratingthe general principles of the invention, since the scope of theinvention is best defined by the appended claims. Intracranial reservespace is an anatomical phenomenon describing the volume of intracranialspace filled with cerebral spinal fluid (CSF). As used in this patentapplication, the term “intracranial reserve space” or “ICRS” refers toall spaces within the cranium that would normally be filled withcerebral spinal fluid when the subject is healthy. This includesconvexital ICRS, brain's basal surface ICRS, including basal cisternsand intracerebral ICRS, i.e. brain's ventricles. ICRS is therefore notlimited to the convexital surface and subarachnoid space around thebrain, but also includes the ventricles, cisterns and sulci that the CSFnormally fills when the patient is healthy. However, the ICRS capacityas used herein is not the actual true volume of the total ICRS asdefined above but is rather merely the available capacity of the ICRSuntil the ICRS is deemed “occupied”, either as a result of implementingthe present invention by blocking venous blood from exiting the cranium,or as a result of an abnormality such as a SOL (space occupying lesion).The ICRS is deemed “occupied” by the present invention when the ICPwaveform amplitude (or other selected variability parameter of the ICPwaveform) compress to the point of being flattened. It is noted thatalthough the CSF inside the ICRS is a liquid and as such isincompressible, the “occupying” of the ICRS by either (i) extra venousblood blocked from exiting through the internal jugular vein or by (ii)a SOL, causes the CSF to be “pushed out” of the ICRS and to exit thecranium into the spinal canal. However, due to the space limitations ofthe spinal canal, only a small portion, approximately 5-10 cc out of70-80 cc, of the CSF exits into the spinal canal before the ICRS isconsidered “occupied” and the amplitude or other variability indicatorof the ICP waves flatten. “ICRS capacity” is the capacity, in volume,that the ICRS can hold from the extra volume of intracranial blood thatis blocked from exiting the cranium after partial occlusion of the IJVuntil the variability (for example amplitude) of brain tissue pulsationsdeclines by a predefined level. Accordingly, the “ICRS capacity” as usedherein is not the actual true volume of the total ICRS but is rathermerely the available capacity of the ICRS (for example to hold extravenous blood) before the variability parameter such as amplitude of theICP waves flatten (as defined quantitatively) and the ICRS is deemed“occupied”. The ICRS is deemed “occupied” when the ICP wave amplitude(or other selected variability parameter of the ICP waves) compress tothe point of being flattened (as defined by the user preferablyquantitatively, or in other embodiments visually).

The present invention generally provides a portable inexpensivedevice/system and method configured to noninvasively measure, in someembodiments to non-invasively measure repeatedly, an ICRS parameter suchas the time to occupy the ICRS or the volume capacity of the ICRS byexamining the brain tissue multidimensional pulsatile activitynoninvasively using ultrasound waves. The device is highly accurate andhas high resolution. It is believed that soft tissues and fluidcompartments exhibit their own characteristic resonant responses toheart systolic and arterial pressure pulses radiating through thetissues of the body (input signal). When a target tissue is stimulatedby specific ultrasound signals, the nature of the reflected ultrasoundenergy waves that bounce back from the tissue depends on the resonantstate of the tissue (output signal). The pulsatile pattern of resonanceresponses of a tissue to specific ultrasonic stimulation is thencollected and interpreted through specific mathematical algorithms toprovide information about the physiological properties of the tissue.The device, method and system provides a dynamic high accuracy and highresolution technique for intracranial reserve space parametermeasurement in some embodiments using ultrasound pulsatility and a skullshape adjustable ultrasonic dual frequency probes, for exampleneedle-like dimensional array of piezocrystals lying on a rectanglestrip shape and operating on different, relatively low, transmittingfrequency and receiving frequency mode. Reflected ultrasonic energy isconverted accurately to signals providing data corresponding tononinvasive dynamic, multiaxial pulsatility activity, intracranialreserve space and in some embodiments intracranial pressure (ICP) in thepreselected volume of tissue.

Some non-limiting advantages of certain embodiments of the presentinvention include its high resolution and accuracy,being portable,noninvasive, dynamic (i.e. can be repeated within relatively short timeintervals such as an hour or even 10 minutes or less), inexpensive, andutilizing easy to operate instruments. It has the ability to measure theintracranial reserve space and determine quantitatively thephysiological status of any brain tissues or fluid compartments evenbefore elevation of the ICP level occurs in some embodiments. Thus,reduction of ICRS is useful as a preventive measure and allows newadditional and recurrent investigation of patient and preventivetreatments. Additional modalities are available for degree of occupationICRS and prevention of future ICP elevation. The present invention, incertain embodiments, detects a significant change, for example loss, ofcapacity (volume) of the intracranial reserve space (ICRS) (“ICRScapacity”), which is most commonly seen from swelling or a growthassociated with a contusion, a cranial tumor or a stroke. If theseconditions are left unchecked, they may be fatal. A loss of ICRS volumecan occur within minutes or hours.

Further, spectral data (i.e. ultrasound cerebral pulsatilespectroscopy-USCPS) can be easily obtained to provide additionalinformation on the tissue composition and structure. The versatility ofthe present invention allows it to be used to aid in diagnosis andprovide information to direct the most appropriate course of therapysuch as in unilateral traumatic contusions, intracranial hemorrhages,brain tumors, cerebral vascular accidents (CVAs), etc.

In a broad embodiment, the present invention is a medical diagnostictool based on ultrasound waves that has the capability to generateimportant diagnostic information non-invasively and dynamically aboutthe physiological status of virtually any fluid space, tissue, or organof interest tissues anywhere in the body including within the brainvolume, intra-abdominal pressure (IAP), and intra-urinary bladderpressure (IUBP).

Prior art methods for ultrasonic viewing of human tissue, typicallyutilize ultrasound pulses of one dimension, which are limited in theultrasound intensity (allowable by government regulation) to beapproximately 120 mW per cm². This was thought to be the onlyappropriate ultrasonic properties for penetrating the skull, and it wasthought that two dimensional ultrasound could not penetrate the adulthuman skull due to considerable ultrasound power attenuation at the highfrequencies (over 3 MHZ). In contrast, the present invention nowsuggests use of two or three dimensional ultrasound, which can be usedto penetrate the skull for example at the intensity of 40-100 MiliW/percm², which is the new FDA regulatory requirement for intensity. Thethree-dimensional pulsations of brain tissue that are output in someembodiments of the present invention improve over the imaging of U.S.Pat. No. 6,328,694 by the present inventor also in that the imaging inthe '694 patent is derived from only vertical pulsatility, whereas inthe present invention the tissue pulsatility is generated in accordancewith some embodiments from each multi-axial direction, including evenoblique directions in some embodiments. This provides more data and moreaccurate imaging.

In still further contrast to the prior art, in some embodiments, as aresult of use of dual frequencies of the ultrasound probe 20 applied tothe head, so that in transmission mode the emitter uses a lowerfrequency and the receiver uses a higher frequency, one obtains greaterdepth of penetration of the ultrasound waves. In addition, this reducesblack noise and improves ultrasound spatial and image resolution andquality. This transmission mode (parallel, continuous mode of theultrasound beam) of ultrasound investigation causes activation ofdifferent anatomical targets of brain and these activated targetsgenerate new multi-frequency intracranial ultrasound beams which aredistributed in multiple directions within the intracranial cavity. Thereflected beams and integrative recordings and stratification of the twodifferent kinds of beams achieve much better image quality, elevatedcoefficient signal/noise ratio and improved quality of resolution andimaging. Specifically, this achieves receipt of much clearer images ofthe brain for evaluating the brain's midline shift and the size of brainventricles and this provides better temporal resolution of multiaxialbrain pulsatility and spectral analysis.In further contrast to the priorart, for example transcranial Doppler (TCD), which requires, and isdependent on, the expertise of the operator who operates the system, andin contrast to other prior art methods and devices requiring significantexperience to interpret the results, the claimed invention is notdependent on such operator expertise and consequently the accuracy ofthe resulting measurements is not dependent on the operator's expertise,once the operator has been trained to use the present invention. Forexample, determination of the compression of the ICP waveform to apredefined degree can in some embodiments be determined by the computersystem using software such as special purpose software. In furthercontrast to the prior art such as TCD and other prior art methods, whichdepend on the professional evaluation of the results and/or requirecomplicated algorithms to interpret the results, the claimed inventionis not dependent on professional evaluation of the results. Even if incertain embodiments one utilizes a visual observance by the user thatthere has been a partial occlusion of the IJV as seen from the imagingof the IJV, or that the variability of the amplitude of the ICP waveformhas flattened, that is a clear visual determination that the operatorcan make quickly without extensive interpretation. In further contrastto the prior art methods and devices for measuring and monitoring theICRS, such as MRI and CT, which require large and expensive equipment ina hospital or clinic, the present invention in certain embodiments is aportable bedside apparatus that non-invasively and dynamically measuresand monitors the intracranial reserve space (ICRS) of a patient, and ina typical case, a technician or nurse or even a layman can be trained touse it. In some embodiments this training can be completed in severalhours.

For a suspected head injury, the present invention is able in certainembodiments to detect a significant loss of volume of the ICRS forexample from swelling associated with a contusion, a cranial tumor or astroke, which if left unchecked may be fatal. Occupation of thepatient's ICRS volume can occur within minutes. Monitoring ICRS and ICPin ER rooms may well dramatically improve neurosurgery by allowingearlier detection and diagnosis of space occupying lesions. In certainembodiments, the present invention is also helpful in treatment of otherneurological conditions including stroke, brain tumors, impairedconsciousness, hydrocephalus, central nervous system diseases andintracranial injury. Knowing the ICRS and ICP non-invasively anddynamically is useful to determining the course of treatment fornumerous conditions of the brain and head. For example, differenttreatments are provided to patients with elevated ICP than patients withlower ICP.

In still further contrast to prior art methods of measuring ICRS, whichrequire a neuroradiologist to be present personally, the method anddevice of the present invention can be implemented by a technician orothers trained in its use. In further contrast to prior art non-invasivemethods, which cannot be used dynamically, the present invention can beused dynamically, i.e. repeated within days, hours or even minutes. Thismeans the measurements can be repeated after a relatively short amountof time, much shorter than for a brain MRI (or for a brain CT). Dynamic,non-invasive monitoring of ICRS parameters (such as the length of timeit takes for the ICRS to become “occupied” or the available volume orcapacity of the ICRS) opens up the possibility of treating patientsbefore ICP elevation or clinical deterioration occurs and in some casesbefore 80% occupation of ICRS occurs. MRI, for example, is not availableto be used dynamically (repeated use during short intervals of minutesor hours or days), and is expensive and time consuming. MRI and CTcannot be used continually or be available near the bedside, and areavailable only in focal hospitals and not in peripheral medical clinics.Due to these disadvantages, CT and MRI are impractical for wide clinicaluse for non invasive measurement and dynamical monitoring of ICRSparameters. A CT scan is also too dangerous for repeated use. Today, noteveryone who needs an MRI receives it. But if ICRS monitoring alreadypointed to a reduced or an elevated ICP, the MRI or CT would bejustifiably given and treatment could be advanced. If even a patientwith a headache were shown to have a much smaller than expected ICRS, aCT or MRI would be run and if it showed a SOL growth, emergency surgerycould be considered. This could allow surgery at an earlier stage priorto clinical deterioration thus improving the expected outcome ofneurosurgical interventions, which is highly dependent on the health ofthe patient.

If a patient has a Space Occupying Lesion (SOL), such as anintracerebral hemorrhage (ICH), a brain tumor, a brain contusion orbrain swelling, these lesions do not immediately result in an elevatedintracranial pressure (ICP). For example, a space occupying lesion (SOL)may progress through multiple stages as follows: during the first stage,the lesion begins occupying the nearest convexital ICRS. Further growthof the SOL during a 2nd stage may cause depression of the walls of theventricles of the brain experience and ventricular asymmetry. The 3rdstage is depression of basal cisterns. The fourth stage is a shift of 2to 5 mm in the brain's midline, called BMLS. The fifth stage is a BMLSof 5-10 mm and the 6^(th) stage is a BMLS of 10-15 mm or more.

It is important to note that during the first four stages of the growthof a space occupying lesion (SOL), clinical signs are very difficult toobtain and symptoms of disease are very difficult to discern. Although apatient may have a large-sized SOL as a result of stages 1-4 of SOLgrowth, compensatory mechanisms of ICRS, namely the ICRS volume andcerebral spinal fluid (CSF) outflow from the head, may prevent clinicalmanifestation of signs of ICRS occupation and elevated intracranialpressure (ICP). This is especially true of elderly patients who haveelevated ICRS capacity since during aging, ICRS grows due to central andperipheral brain tissue atrophy. Accordingly, dynamic evaluation of ICRSand changes in ICRS, may provide crucial information even beforemanifestation of ICP elevation. ICRS parameters such as the extent ofreduction in the volume of ICRS, for example from a SOL, or the lengthof time until ICRS is occupied (as defined by variability declining by apredefined amount) by partial occlusion of the IJV for example, are goodpredictors of neurological developments of the patient, before clinicaldeterioration, and has significant prognostic value in neurosurgery.Specifically, reduction of ICRS may well indicate that in the nearfuture the patient will develop an elevated ICP and/or will experienceclinical-neurological deterioration, something the prior art does notachieve. Consequently, ICRS monitoring may well be a more sensitivemarker than ICP monitoring for patients with acute and chronic SOLgrowth. ICP elevation occurs after ICRS occupation and patients with ICPelevation already have experienced significant clinical deteriorationrequiring immediate surgical intervention. Furthermore, a significantreduction of the patient's ICRS within a short time interval is anindicator justifying recurrent CT investigation. Even withoutclinical-neurological deterioration, dynamic monitoring of ICRS is animportant additional tool for neurologists and neurosurgeons justifyingrepeating a CT, even when the previous CT occurred 10-15 minutes ago,something that normally would not be allowed under CT guidelines. Therepeated CT can also save previous time consumed by discussions betweenradiologists and other colleagues as to whether to repeat a CT.

Note that in contrast to reduction of ICRS from a first measurement to asecond measurement (especially in a relatively short time interval)which may well indicate future elevated ICP or clinical deterioration,in adults, if based on a single measurement the ICRS is found to be high(based on length of time (T) or based on absolute ICRS capacity), thisalone would indicate that intracranial pressure is likely to be low ornormal and conversely, if the ICRS is found to be low (based on lengthof time (T) or based on absolute ICRS capacity) in a single measurement,it indicates that intracranial pressure is likely to be high or normal.In further contrast to prior art techniques, certain embodiments of thepresent invention may also be useful as a general check-up for healthyindividuals. For example, a CVA (stroke) is common among the elderly andcan be prevented in high-risk patients or can be efficiently treated ifdetected in a timely manner As a bedside noninvasive apparatus whichdoes not involve high levels of radiation, the apparatus of the presentinvention can be used to perform routine preventative screening on theelderly.

The principles and operation of a Non-Invasive Dynamic Measurement ofIntracranial Reserve Space according to the present invention may bebetter understood with reference to the drawings and the accompanyingdescription.

In this patent application, the term “intracranial brain tissuepulsation waveform” or “ICP waveform” refers to the wave function thatis obtained, and in some embodiments displayed, when the signal from theultrasound probe placed on the subject's head (in some embodiments inboth a horizontal position and in a vertical position) is adapted bysoftware 55, such as special purpose software 55, of the computer system50 of the present invention to show real time images of brain tissuepulsation. For example, the ultrasound probe 20 provides brainpulsations, such as two-dimensional brain pulsations, that are adaptedby software, i.e. in some embodiments by first applying the fast fouriertransform (FFT) and then applying the inverse fast fourier transform(IFFT), to yield two-dimensional pulsatility which in some embodimentsis further converted to three-dimensional pulsatility by includingsignals from both horizontal and vertical positions held by the probe.The additional dimensions provide more information and more accuratelycapture the brain tissue and its real-time movements. For example,intracranial pressure and intracranial reserve space are more precise byusing both dimensions since horizontal pulsations may be moreinformative both for ICP and for the compression of the waveform usedfor ICRS. Multi-dimensionality, i.e. even further dimensions such asoblique directions, may be included utilizing computer science.Accordingly, the intracranial brain tissue pulsation waveform used inthe present invention takes into account brain tissue pulsations,arterial blood flow input and venous blood flow output. In someembodiments, it also takes into account cerebral spinal fluid (CSF)outflow.

“ICP waves” refers to the waves of the ICP waveform.

Referring now to FIGS. 1 through 3, there are shown an example of asystem for observing ICRS in a volume of tissue in a subject inaccordance with one embodiment of the present invention.

FIG. 2A shows on the left a brain MRI to help visualize where theultrasound reflections come from. The right side of FIG. 2 shows an echoencephalogram with real-time pattern of brain pulsation from ultrasoundimaging using a one-dimensional A mode ultrasound probe. It is possibleusing the computer system of the present invention to derive ICPwaveform directly from the one-dimensional signal on the right of FIG.2A. This is less expensive that a two-dimensional ultrasound probe 20.However, it is also less accurate since it is derived from aone-dimensional probe and also because it is not derived from an image.

FIG. 2B shows a sectional view in the middle of the figure having areal-time image of multi-dimensional brain tissue pulsation from atwo-dimensional ultrasound sector imaging probe 20. On the left of FIG.2B and on the right of FIG. 2B are ICP waveforms derived from the imagein the middle. Although more expensive, these ICP waveforms are moreaccurate because they derive from an image and because they derive froma two-dimensional ultrasound probe. Both the graph on the right of FIG.2A and the graphs on the left and right of FIG. 2B represent thereflected ultrasound energy which is detected from a selected pixel inthe tissue at different depths and exhibit the pulsatile activity(differential between emitted and reflected ultrasound energy−braintissue's ultrasound energy shift) as a function of time. As shown, someobservation of pulsatile activity will vary with orientation ordirection of the observations.

In a healthy individual, it takes time, for example about 3 seconds(depending upon age and other factors) for the intracranial reservespace to be occupied by the blockage of blood outflow to the IJV. In apatient with some of the ICRS already occupied by a pathological growth,the time to “occupy” the ICRS by the extra blood would be significantlyless.

The time interval for occupying the ICRS after partial occlusion of theIJV is a measure of how long it takes to “occupy” the intracranialreserve space from when the mild pressure applied at the neck of thesubject on the IJV causes the partial blockage of blood outflow out ofthe cranium. For a normal adult, taking into consideration age and ifdesired other suitable factors, it takes about 3 seconds to “occupy” theintracranial reserve space when the blood flow out of the brain isaffected by partially occluding the IJV. If the subject's intracranialreserve space instead took only one second to become “occupied”, forexample, it could indicate growth of an SOL within the cranium that hadreduced the volume of the ICRS already before the partial occlusion ofthe IJV. If on the other hand it took too long, for example 7 seconds,that could indicate that the intracranial reserve space was too large.If it took 2 seconds for the ICRS to become “occupied”, the measurementis repeated, at least according to one embodiment. If the ICRS is foundto be constant based on receiving similar results from multiplemeasurements, then if the deviation from 3 seconds is small enough, forexample 2 seconds or 4 seconds, then the subject may be considered tonot be in danger. This conclusion is only one non-limiting example of amedical conclusion that may be made from the additional usefulinformation provided by the present invention.

Referring now to FIG. 3A, there is shown a non-invasive measurement ofthe ICP as well as non-invasive measurement of amplitude of ICP waveformcompression of brain tissue pulsation which is guided by images ofpartial occlusion of the internal jugular vein (IJV). Stepwise partialocclusion of IJV is performed for example on a supine patient inaccordance with one embodiment of the present invention, under guidanceof 2D-ultrasound imaging. In some embodiments, the jugular vein probe35A emits ultrasonic frequency within the range from 3.5 MHz to 24 MHz.In some embodiments, the device includes a stepper motor, and on theopposing side, a digital manometer to determine how much pressure wasplaced on the IJV.

As shown in FIG. 3A, the present invention is in certain embodiments asystem for monitoring intracranial reserve space. FIG. 3A shows oneembodiment of the system 10 of the present invention including a displayscreen 57 (forming part of the computer system 50) upon which is shownside by side: the ultrasound reading taken from the IJV probe 35A;pulsatile views of the cranium from the probe 20 including an externallyplaced cranial location marker; a compressional ICP waveform graphshowing the minimal/maximal amplitude (or other waveform parameter) ofthe ICP waveform.

System 10 includes in some embodiments an ultrasound probe 20 forapplication to the cranium, an instrument 30 for applying pressure tothe neck of the subject and a computer system 50 for processing signalsgenerated by the ultrasound probe 20 and for determining an intracranialreserve parameter. In some embodiments, the ICRS parameter is an ICRScapacity measuring an absolute volume as determined by the volume ofvelocity of venous blood outflow blocked multiplied by the length oftime (as described below) from a partial occlusion of the IJV until theICP waveform compresses to a predefined extent as measured by a declinein its variability and further adjusted by multiplying by a percentageof the cross-section of the IJV that has been partially occluded. Inother embodiments, the ICRS parameter is a length of time determined bya calculation made by the computer system 50.

In certain embodiments, system 10 for non-invasive monitoring of anintracranial reserve space (ICRS) parameter of a mammalian subject,comprises an ultrasound probe 20, such as a multi-frequency ultrasoundprobe 20, that is configured, beginning at a start time, to emit andreceive ultrasound waves into and from a head of the subject and toproduce a signal corresponding to brain tissue pulsation. System 10 insome embodiments also includes an instrument 30 configured tonon-invasively apply a pressure to effectuate a partial occlusion (or adeformation of the walls) of an internal jugular vein of the subject,the partial occlusion starting at the start time. The instrument 30 alsoincludes in some embodiments a second probe 35A (called “second” only inthe sense that probe 20 is the first probe), such as an ultrasoundprobe, configured to produce a second signal from which computer system50 derives images, for imaging the internal jugular vein to see when thepartial occlusion started. The imaging by the computer system is forexample for imaging a cross-section of the internal jugular vein, or forimaging another view of the internal jugular vein that allows thecross-section (or in other embodiments allows the diameter (or even someother parameter of the IJV sufficient to reveal when the partialocclusion starts)) of the internal jugular vein to be monitored to seewhen the partial occlusion has started. The jugular vein probe 35A emitsand receives at a frequency within the range of 3.5 MHz to 24 MHz,according to certain embodiments. The emitting frequency may be the sameas the receiver frequency in the case of the jugular vein probe 35A.

When the partial occlusion has been determined to have started, in someembodiments the user can push a timer. Alternatively, the computersystem 50 can determine when the partial occlusion of the IJV hasoccurred (because the computer system 50 is also configured to receivethe second signal and to derive from the second signal images of theinternal jugular vein) and automatically start the timing function. Insome embodiments, the computer system 50 simply records the time or theamount of time, such as seconds or milliseconds elapsed, throughoutbeginning when the partial occlusion starts. These are non-limiting ofways of measuring the length of time (T), as defined below.

System 10 in some embodiments also includes a computer system 50configured with all suitable hardware and software necessary to receivethe signal from the ultrasound probe 20 configured for the subject'sskull 11 and to receive an output of a start time of the partialocclusion of the internal jugular vein of the subject. Computer system50 in some embodiments is also configured, for example using one or moreprocessors 52 and software 55, such as special purpose software 55, andall suitable and necessary hardware and software including memorystorage 54, to derive from the signal an intracranial brain tissuepulsation waveform, and to monitor time so as to determine a length oftime from the start time to a subsequent time at which the waveform issufficiently compressed so as to exhibit a predefined decline invariability. The software 55 for deriving the intracranial brain tissuepulsation waveform from the signal of the ultrasound probe 20 is knownor readily adaptable from known software associated with single ortwo-dimensional ultrasound probes. Computer system 50 also includes insome embodiments all suitable hardware and software for displaying braintissue pulsatility, such as the ultrasound device shown in FIG. 1A.

“Deriving” the ICP waveform from the signal of probe 20 includesderiving it directly and includes deriving the ICP waveform from thesignal indirectly. In one embodiment, computer system 50 indirectlyderives the ICP waveform from the signal generated by probe 20 byderiving the ICP waveform from an image of brain tissue pulsationwherein the image of brain tissue pulsation had been derived from thesignal generated by probe 20. In a different embodiment, computer system50 directly derives the ICP waveform from the signal generated by probe20, which typically is a two-dimensional probe 20 but can also be aone-dimensional probe 20.

FIG. 9 shows an intracranial brain tissue pulsation waveform startingwith a certain variability in amplitude, beginning to compress orflatten and continuing until the variability, as measured in terms ofamplitude, is compressed after 19 seconds. In some embodiments, certainportions of computer system 50 (for example one or more processors ordisplay devices) are remote from the other parts of system 10 andconnected by wired or wireless communications for example nearby but inanother room of a hospital department, or in other cases more remote andin communication over the Internet. If all portions of system 10 are inone place and connected, system 10 can also be referred to as anapparatus 10 or device 10.

Pressure to the IJV applied in accordance with the present invention insome patients initially causes an elevation of the amplitude of brainpulsation. Additional applied pressure results, in these patients, in adecrease of amplitude to a more compressed line. Pressure to IJV causesa decrease of pulsation variability in the brain until it becomes arelative straight-line. The amount of time until this happens correlateswith the magnitude of the original ICRS capacity.

While amplitude of the ICP waveform has been discussed, this is not theonly measure of ICP waveform variability useful for the presentinvention. In one embodiment, variability of the intracranial braintissue pulsation waveform comprises at least one of the following ICPwaveform parameters: (i) a variability of an amplitude of the waveformand (ii) a variability of an area under the curve of the waveform, (iii)a variability of a dominant frequency of the waveform (for example afrequency between 0.1 and 35 MHz), (iv) a direction of high frequencyshift (for example of between 12 and 35 MHz) of the waveform (whichaffects the amplitude and hence variability of the waveform), (v) aphase shift of the waveform (which affects the amplitude, and hencevariability, of the waveform and (vi) a variability of a multiaxialspectroscopy of the waveform (ICPWMS). In another embodiment,variability of the intracranial brain tissue pulsation waveformcomprises a variability of at least one of the following ICP waveformparameters: (i) an amplitude of the waveform, (ii) an area under thecurve of the waveform, (iii) a dominant frequency of the waveform (forexample a frequency between 0.1 and 35 MHz) and (iv) a multiaxialspectroscopy of the waveform (ICPWMS). The spectroscopy referred toherein is a mechanical motion (pulsatility) spectroscopy, not a magneticor electrical spectroscopy. Other functions that quantify variability ofthe ICP waveform are also within the present invention, including butnot necessarily limited to combinations and/or derivatives of the abovesix examples of ICP waveform variability indicia/parameters.

In order to determine if the amplitude or other characteristic of theintracranial brain tissue pulsation waveform has reached a predefineddecline in variability, for example as shown in FIG. 9, according to oneembodiment, a comparison of variability during a predefined period oftime is made with a previous variability during a preceding period oftime and this is performed by one or more processors of the computersystem 50, in accordance with special purpose software. Variability isdefined, according to one option, by the difference between the highestand lowest amplitude (or other waveform variability characteristic)during a certain period or cycle. For example, the predefined decline inICP waveform variability is defined such that variability of anamplitude (or of other waveform parameter indicative of variability) ofthe waveform during the predefined period of time is ten percent (or inother embodiments 5%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%) oris no more than ten percent (or in other embodiments no more than 5%,15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%) of a variability during aprevious period of time of predetermined length. In other words, thewaveform has compressed to such an extent that its variability is only10% of what it previously was, for example during a previous cycle. Inone example, the predefined decline in variability of the waveform isdefined such that the waveform has compressed 80% such that itsvariability has become only 20% of what it was previously.

In some embodiments the “previously” that it is compared to is thevariability of the waveform during a previous cycle, or in otherembodiments during an average of certain previous cycles such as anaverage of the variability during the preceding 2 cycles, or during thepreceding 3 cycles, or during the preceding X cycles, wherein X can beany positive integer.

In another example, the predefined decline in variability is definedsuch that once the decline in variability has persisted for at least acertain amount of time or at least a certain number of predefinedperiods of time or cycles, only then is it counted as having achievedthe required decline in variability. Since the predefined decline invariability is quantified, according to one embodiment, the computersystem signals that the interval end time has been reached, therebytriggering the computer system to calculate the time interval, whichrepresents how long it took for the ICRS to become “occupied”.

The pressure application instrument 30, in some embodiments, isconfigured to also measure the pressure at the internal jugular vein(IJV) using a manometer 39, as shown in FIGS. 3, FIG. 6 and FIG. 8.Instrument 30 is configured in certain embodiments to apply an initialpressure and subsequent greater pressures in uniform stepwise incrementsto the internal jugular vein. For example, in one particularnon-limiting embodiment, an initial pressure of 1 mm Hg is first appliednon-invasively at the subject's skin at the IJV (at the neck), then apressure of 2 mm Hg is applied, then 3 mm Hg, then 4 mm Hg, then 5 mmHg, and this stepwise upward progression is continued until thepredefined decline in variability of the intracranial brain tissuepulsation waveform is detected from the display visually by the humanuser, or more preferably automatically by the computer system when thespecial purpose software measures the variability of the waveformdynamically. The detection of the compression in the waveform to apredefined decline in variability is one or a combination of (i) avisual detection by the user and more preferably (ii) a predefined alertby the computer system according to quantitative criteria written intothe software 55, for example special purpose software 55. The alert maybe based on at least one of (i) the length of time (T) and (ii) anintracranial reserve space capacity. It may also be based on the amountof pressure applied by instrument 30.

The instrument 30 is shown in FIGS. 6-8. Instrument 30, as shown in FIG.8, is a pressure applying and pressure sensing device guided by a2-dimensional ultrasound image for highly accurate pressure measurementon a cavity, vessels and tissue of a subject. As shown in FIG. 6 andFIG. 8, in certain embodiments one way of implementing this is that theincremental increases in pressure driven by a motor 31 and piston 32causes air or another fluid to travel through tube 47 and to a tripleangle connector 49. In some embodiments there are multiple pistons, asis known in the art of controlled fluid dispensers such as syringes.Some of the fluid then travels past the triple connector 49 to manometer39 while other portions of the air or another fluid enters pipe 40. Insome embodiments, the incremental increase in pressure in pipe 40 causespipe 40 to pivot at pivot point P (FIG. 6) and flex on its axis withholder 41. Holder 41 is in some embodiments fixed to a static structureby a fixing component 44 (FIG. 8). This pivoting or rotation of pipe 40also generates a forward linear motion by probe 35A against the neck orother body part of the subject incrementally.

In some embodiments, pipe 40 has an inverted piston 42 movable withinit. Inverted piston 42 may be attached on its distal end, as shown inFIG. 6 and FIG. 8, to probe 35A. Although FIG. 6 depicts the connectionbetween probe 35A and inverted piston 42 as linear, in certainembodiments, the connection between probe inverted piston 42 and probe35A in certain embodiments permits a change of angle between probe 35Aand inverted piston 42. For example, in one embodiment, along theconnection between probe 35A and inverted piston 42 is a joint 42A thatpermits multiple degrees of freedom, including in one embodiment sixdegrees of freedom, for probe 35A, something that facilitatesmanipulation of probe 35A through forty-five degree or other angles inaccordance with Dopplerography. In FIG. 8, for example probe 35A isangled relative to inverted piston 42.

The instrument 30 in some embodiments shown in FIG. 7 includes a motor31, at least one piston 32 movable within a housing 33 such as a syringe33 (having syringe cover 33A), a source of liquid or gas fluid 34, forexample air, and an applicator 35 whose distal end 36 is shaped toengage the neck of the subject. The applicator 35 includes an ultrasoundprobe 35A (not to be confused with probe 20 used at the head of thesubject) whose signal is converted to an image of the UV. Ultrasoundprobe 35A includes in some embodiments a Doppler ultrasound output formeasuring the linear velocity of the blood flow at the IJV. This makesit possible to obtain the ICRS parameter of ICRS capacity which dependson linear velocity of the IJV. Without this Doppler ultrasound output itis possible to obtain the ICRS parameter of length of time (T) for ICRSto be occupied although not the ICRS parameter of the ICRS capacity. Asseen from FIG. 8, motor 31 is connected to a power supply 38 and acharger in some embodiments. FIG. 8 also shows digital manometer 39A toshow a digital version of the pressure and computer 46 along withbattery charger. The computer interacts with compressor 43 (FIG. 6A) ormotor 31 (FIG. 6, FIG. 7) to determine what volume of fluid, such asair, to send to the pipe 40.

FIG. 6A shows a different embodiment of instrument 30 in which animpulse compressor 43 produces uniform amounts of air that can beincrementally adjusted as in FIG. 6.

The multi-dimensional probe 20 is a modified version of a standard USBcompatible ultrasound probe, such as a modified version of the standardUSB compatible probes manufactured by Interson corporation ofCalifornia. Probe 20 preferably should be modified in several ways, inaccordance with some embodiments. First, as shown in FIG. 1C probe 20has in some embodiments a mechanism for dispensing a gel. For example,probe 20 in some embodiments has an automatic gel dispenser 26 which mayinclude a gel reservoir 28, a tube 26b for gel transfer, amicromotor/microengine 29 and an actuating mechanism such as a button26a. Second, as shown in FIG. 1C, the distal end of the probe 20 isconfigured to grip the skull 11. For example, in some embodiments thedistal end of probe 20 is concave and has a shape that is adjustable soas to conform to an outer surface of the skull 11 of the subject. Insome embodiments, for example, one or more springs 27 (FIG. 1C) aresituated behind and connected to each piezoelectric crystal 22—or groupof crystals—of the crystal array 22 of the probe 20. Third, the probe 20is a multi-frequency probe whose emitter and receiver have differentfrequencies. In one example, the emitter has a frequency of 0.5 to 2 MHzand the receiver has a frequency of 1 to 4 MHz which may be double thefrequency of the emitter frequency in some embodiments.

In addition, in some embodiments shown in FIG. 3B the probe 20 has onlya transmission mode having continuous voltage in which the emitter 20Aof probe 20 is on one side of the head and the receiver 20B of probe 20is on the opposite side of the head of the subject. In a differentembodiment shown in FIG. 3C, probe 20 has both a continuous transmissionmode (called “transmission mode”) and a discrete transmission mode(called “impulse mode”) which can be referred to as integrative mode inwhich the emitter and receiver of probe 20 are adjacent and preferablyintegrated into one device and applied to one side of the head. Theimpulse mode involves discrete non-continuous application of voltage.For example, as shown in FIG. 1B, a central section of the probe 20having the central piezocrystal array 22 emits in transmission mode andthe side (lateral) sections of the probe 20 having the side piezocrystalarrays 22A receiver at a different frequency and in impulse mode. Thisis also integrated into one device. The integrate mode is better becausethe signal to noise ratio is ratio is much higher and signals emittedare amplified. Since the different parts of the head are non-homogeneousand have different acoustic impedance, the border points between thematerials of different impedance generate reflecting waves in differentdirections toward the receiver of the probe 20.

The two-dimensional USB port compatible probe 35A of instrument 30 usedfor imaging the internal jugular vein to see (for example to see when itis partially occluded) is an ultrasound probe that in some embodimentshas a frequency such as 6-7.5 MHz, or generally between 3.5 MHz and 24MHz. For example, the ultrasound probe 35A transmits the signal to thecomputer system and the computer system presents to the user a dynamicimage of the internal jugular vein. The image preferably is of across-section of the IJV. The cross-sectional area of the IJV, or inother embodiments the diameter of the IJV, is determined eitherautomatically by the computer system 50 or estimated by the uservisually from the image produced by the display.

Both probe 20 and single frequency probe 35A may be structured such thatthe electronics, which is heavy, is distanced by a connecting cable fromthe piezoelectric array of crystals to provide greater flexibility inuse of each of the probes 20, 35A. The cable is grounded to blockinfluence from an EMF field. Preferably, both the two-dimensional probe20 and the singe frequency probe 35A are mechanical scanning probes thatmove the emitters and receivers. The sector of the image generated bythe probe 20 is shown in FIG. 3A. In another embodiment shown in FIG.1B, static arrays of emitters and receivers having a shape that providesthe sector is depicted. FIG. 1B shows both a central piezocystal array22A and lateral piezocrystal arrays 24. The lateral piezocrystal arraysare also called side piezocrystal arrays. There is, in certainembodiments, as shown by FIG. 1B an angle between the centralpiezocrystal array 22A and the lateral piezocrystal arrays 24. Thisangle is 10 degrees on one side and 15-20 degrees on the second side, insome embodiments. This difference in angles provides greater versatilityfor probe 20 since skulls vary amongst humans.

As shown in FIG. 1CA, as an alternative embodiment to that shown in FIG.1C, springs 27 are situated on each horizontal end in order to maintainthe piezoelectric crystals 22 that are at the ends of the crystals 22facing the skull 11 of the subject (as opposed to the ends facing thesprings 27). Since the skull 11 may vary from one person to another,each group of piezoelectric crystals other than the central group has aseparate spring 27 adapted to cause the array of crystals to engage theskull 11.

As seen from FIG. 7, the instrument 30 is connected to a manometer 39.This provides the IJV pressure for calculating the ICRS per pressure. Insome embodiments, the ICP is also measured and the combination ofparameters is used to determine medical decisions. For example, if theICP is known to be low enough then it is recommended to measure andmonitor ICRS.

Referring now to FIGS. 1A through 1C, there are shown, by way ofexample, a novel ultrasound probe 20 used for intracranial spacemeasurement in accordance with one or more embodiments of the presentinvention. In the embodiments shown in FIGS. 1A-1C, ultrasound probe 20is designed to be adjustable to suit the curvature of the skull 11surface, which varies from one individual to another. Thus optimalcontact is assured, for best definition. The probe 20 has ultrasoundmulti frequencies and multi-axial mode. The probe is able to scantowards any spatial angle or dimensional axis (as compared to prior artsingle-dimensional probes). Additionally shown in FIG. 1C, theultrasound probe 20 may include a gel reservoir 28, for example anacoustic gel reservoir, which may be mechanically activated to releaseand apply ultrasound gel upon the skull.

The central part of the probe, shown in FIG. 1B, includes 2Dpiezocrystals 22 with ultrasound carrier frequency of 0.8 MHz, and onthe two sides of probe (receivers) with receiver frequency ranges from 1MHz to 2 MHz, more preferably between 2 MHz and 4 MHz. By selectingsuccessive subset of probes from the array, successive contiguous groupsof probes and successive focal points, a series of pixels within thetissue may be observed which cover the entire volume of the tissue at aresolution dependent on the pixel size. In some embodiments, the probeis moved to various locations upon the skull, and optionally thesesector scans are combined using relevant software, to obtain a scaninclusive of all anatomical regions of import. Certain embodiments ofthe present invention are thus equivalent to ultrasound computertomography, without its disadvantages, such as that the claimedinvention can be implemented dynamically and without harmful radiation.

As shown in FIG. 1B, ultrasound probe 20 in some embodiments isconfigured in a shape to be held adjacent a skull of the subject forexample at the top of the head. In some embodiments, an adjustableflexible rectangular array 22 of ultrasound piezoelectric crystal array22, for example including lateral piezoelectric arrays 24 and a centralpiezocrystal array 22A, as shown in FIG. 1B, is arranged in acustom-made array in which is brought in contact with the skull. Anadjustable flexible rectangle array of ultrasound probes is arranged ina custom-made array 22 which is brought in contact with the surface ofthe skull more effectively.

In prior art ultrasound probes, the emitter and receiver typicallyoperate within the same frequencies, and thus are unable to penetratethe skull at the typical frequencies (3-10 MHZ) used to view other humantissues. In contrast, in accordance with one particular embodiment ofthe present invention, the emitter of probe 20 may emit at 0.5-3 MHZwhile the receiver of probe 20 receives at approximately 1.0 MHz-6 MHz,which provides a high resolution scan. In accordance with oneembodiment, the probe 20 of the present invention uses a low frequency(0.5 MHz to 3.0 MHz, for example 0.8-2.6 MHZ, for example 1.7 MHz)ultrasound emitted signal as there is little attenuation of the skull atthese frequencies. However, the receivers of probe 20 are high frequencyreceivers in the range of 1 MHz to 6 MHz, more preferably between 1 to 4MHz (which provides high resolution). In general the emitting frequencyis lower than the receiving frequency and in one embodiment bothemitting and receiving frequencies are between 0.5 and 3.5 MHz.Typically, the receiving frequency is roughly twice the emittingfrequency. In one particular embodiment, the ultrasound probe 20 emitsat a frequency of about 0.5 MHz and receives at a frequency of 1.0 MHz.In one other particular embodiment, it emits at 1.76 and receives at 3.5MHz. In one other particular embodiment, the ultrasound probe 20 emitsat a frequency of about 1.0 MHz and receives at a frequency of up toabout 1.7 to 1.8 MHz, and in one embodiment 1.76 MHz, using a carrieremitter frequency of about 0.5 MHz to 1.8 MHz, and in particular anemitter frequency of 0.5 to 1.76 MHz.

As a result of the dual range frequency ultrasound probes, ultrasoundpower is less attenuated by bones through which the ultrasound wavestravel. In addition, the visual spatial resolution of the brain tissueimage is good. For example, in some embodiments the resolution of theICP waveform (or waveform pattern) is more than 3000 points per cycle,for example more than 4000 points per cycle or more than 5000 points percycle or more than 6000 points per cycle This provides an advantage overthe resolution achieved by the prior art, which is 3000 points percycle. Reflected ultrasound energy from the tissue is received via theprobes and then converted into output signals. A high resolution, fastprocessing unit will process these output signals from the probes, anddetermine the pulsatile activity and characterize the response status ofthe tissue target. This information is then transformed intoquantitative measurements of tissue characteristics and intra tissuepressure.

As shown in FIG. 2A (see “point I and “point II”), in some embodiments,multi-frequency ultrasound probe 20 is configured in some embodiments toreceive ultrasound waves from at least two different intracraniallocations. As shown in FIG. 2A, in some embodiment the two differentintracranial locations are dissimilar according to predeterminedcriteria. The computer system 50 is configured in some embodiments todetermine a representative ICRS parameter from separate respective ICRSmagnitudes at the at least two different intracranial locations. In oneembodiment, these two different locations are preferably unlike oneanother, for example one location could be a surface of the cranium anda second location could be the third ventricle (or tissue that islocated between the surface of the cranium and the third ventricle). Inone embodiment, when the user applies probe 20 to a first of thedifferent locations, the user situates the probe 20 horizontally whereaswhen the user applies probe 20 to a second of the different locations,the user situates the probe 20 vertically. In another embodiment, whenthe user applies probe 20 to a first of the different locations, theuser situates the probe 20 vertically whereas when the user appliesprobe 20 to a second of the different locations, the user situates theprobe 20 horizontally. In either of these two embodiments, applying theprobe 20 in both horizontal and vertical positions enhances the accuracyof the data obtained for the ICP waveform.

In some embodiments, computer system 50 is further configured to convertthe signal received from probe 20 into a dynamic image of a pulsatilityof brain tissue, and in particular a multiaxial pulsatility or athree-dimensional pulsatility of brain tissue, in at least a part of thehead that the probe received ultrasound waves from. System 10 includesall hardware and software necessary to implement this, including in someembodiments, special purpose software configured to convert the signalinto multi-dimensional brain tissue pulsations and to derive real timedigital intracranial pressure waves. The multi-dimensional pulsations insome embodiments include all three mutually perpendicular planes formultiaxial directions including in some embodiments multiple obliquedirections in each of the three mutually perpendicular planes. Thedynamic image of brain tissue pulsatility is displayed on a computerdisplay for the user to see. The image of brain tissue pulsatility is acontinuous dynamic image in some embodiments. Some embodiments of thepresent invention provide the possibility of fourfold magnification ofthe images of the brain pulsation, which makes it much easier to seevery tiny pulsations of brain tissue. In some embodiments, this providesvisualization in real time of the brain tissue moving in threedimensions, by means of special purpose software. This provides a visualdisplay of the brain tissue to the physician, technician or user.However, even without this, the present invention is able to determinethe length of time (T) from partial occlusion of the IJV until thevariability of the ICP waveform has been compressed and from this tocalculate the ICRS capacity and whether the ICRS is normal, too large ortoo small.

As a result of the computer system 50 monitoring one or moreintracranial reserve space parameters, and in some embodiments also theintracranial pressure, the computer system 50 is configured to send analert that the ICRS is abnormal such that an action, such as a surgeryis needed or such that clinical deterioration of the subject is eitherpredicted to occur or inferred to have occurred based on an abnormalICRS.

In certain embodiments, the computer system is further configured todetermine a magnitude of an intracranial reserve space (ICRS) parameter.One such parameter is the length of time from the partial occlusionuntil the amplitude or other waveform parameter achieves a predefinedlevel of variability decline, for example flattening out to a predefinedpercent of previous variability. This length of time parameter providesinformation as to whether the ICRS is normal, too large or too small, byinference. This determination of whether the ICRS is too small, normalor too large may consider the age of the subject and other suitablecharacteristics. In some embodiments, this determination considers theICP of the subject, for example an ICP of the subject as determined byan embodiment of the present invention.

In some embodiments, the computer system 50 is configured to determinethe magnitude of an ICRS parameter from a volume velocity (V) of venousblood output occluded at the internal jugular vein (in some embodimentsalso taking into consideration the ICP or pressure at the IJV) takinginto consideration the length of time (T) of application of thepressure. In this case the ICRS parameter is the capacity, in volume,that the ICRS can hold from the extra volume of intracranial blood thatis blocked from exiting the cranium after partial occlusion of the IJVuntil the variability (for example amplitude) of brain tissue pulsationsdeclines by a predefined level. This is called “ICRS capacity”. It isnoted that the blocked venous blood pushes the CSF to exit the craniuminto the spinal canal. Only a small portion, approximately 5-10 cc outof 70-80 cc, of the CSF exits into the spinal canal before the ICRS canbe considered “occupied” and the amplitude or other variabilityindicator of the ICP waves flatten (due to the space limitations of thespinal canal). Accordingly, the “ICRS capacity” as used herein is notthe actual true volume of the total ICRS but is rather merely theavailable capacity of the ICRS (for example to hold extra venous blood)before the variability parameter such as amplitude of the ICP wavesflatten (as defined quantitatively) and the ICRS is deemed “occupied”.The ICRS is deemed “occupied” when the ICP wave amplitude (or otherselected variability parameter of the ICP waves) compress to the pointof being flattened (as defined by the user preferably quantitatively, orin other embodiments visually).

For example, the computer system 50 in some cases makes use of amathematical relationship V·T·C=ICRS volume, which equals the volume ofextra intracranial blood that “occupied” the ICRS due to the partialocclusion of the IJV, wherein V is the volume velocity of venous bloodblocked (volume velocity being linear velocity times cross-section) overT seconds times C, which is the proportion of the IJV that has beenoccluded by the partial occlusion, and which in some embodiments is thepercentage of the cross-section of the IJV that was occluded by thepartial occlusion, for example 0.05 (i.e. 5% occlusion) or 0.10 (i.e.10% occlusion) 0.15 (i.e. (15% occlusion) or another percentage between5% and 25% or in some examples between 5% and 15% of the initial(pre-occlusion) cross-section of the IJV. Note that the percentage ofthe cross-section is a scalar value rather than a variable. The partialocclusion may also be measured by a percentage of the initial(pre-occlusion) diameter (or in some embodiments the radius) of the IJVoccluded, for example 2.5% or 2.5% to 8% of the diameter of the IJV orfrom 2.5% to 13% or from 2.5% to another percentage between 2.5% and13%. Generally, use of the cross-section is more precise than use of thediameter.

The exact percentage of the partial occlusion of the IJV implemented maydepend on the individual. A child or a person with high ICP may be givena partial occlusion of 5%. An elderly person or a healthy patient withnormal ICP may be given a partial occlusion of 20%. These arenon-limiting examples.

Equation (1): ICRS=V·T·C, wherein V is the volume velocity (linearvelocity times cross-sectional area of the IJV) of the blood flowingacross the IJV for example just before partial occlusion, wherein T isthe length of time from partial occlusion until a predetermined declinein variability of the ICP waveform occurred and wherein “C” is thepercentage of the cross-section of the internal jugular vein that hasbeen partially occluded. The cross-section of the IJV and the linearvelocity of the blood through the IJV is determined by the computersystem using a signal of the ultrasound probe 35A of instrument 30having a Doppler measurement feature.

The units obtained are distance cubed, such as centimeters cubed. Theunits of centimeters cubed are derived by multiplying cm/sec (the unitsfor linear velocity) by (cm)² (the units for cross-section) and byseconds (the units for time). Stated mathematically, the units derivefrom: (cm/sec)·(cm)²·sec=(cm)³

The “ICRS capacity” corresponds to the available volume of intracranialreserve space that existed before the partial occlusion of the IJVcaused the extra blood within the cranium to occupy the intracranialreserve space—by pushing the CSF out of the cranium into the spinalcanal—until the brain tissue pulsations were compressed. This volumeparameter, as well as the length of time it takes for the ICRS to be“occupied”, are useful to neurosurgeons and others in makingdeterminations as to the tentative diagnosis of the patient, whattreatment to administer and the prognosis. In accordance with thecertain embodiments of the system and method of the present invention,this parameter is non-invasively measured repeatedly, for examplemultiple times within a period of time of an hour or multiple timeswithin X minutes, wherein X is 15, 30, 45, 60, 75, 90, 120, 150, 180,200, 250, 300, 350, 400 or 500 or multiple times within X hours, whereinX is 0.1, 0.2, 0.3 . . . 0.9 or 1.0, 2, 3, 4, 5, 6,7 8, 9, 10, 11, 12,18, 24, 36, or 48 or a greater number of hours, or daily or weekly orbi-weekly or monthly or bi-monthly or quarterly or semi-annually orannually or at greater intervals. The repeated measurements are atuniform intervals in some embodiments. In other embodiments, therepeated measurements are not at uniform intervals. The ICRS parameter(for example either length of time T or ICRS capacity) is measureddynamically in some embodiments. Each time the ICRS parameter ismeasured, the instrument 30 is applied to the internal jugular vein ofthe patient again. However, the length of time that this pressure isapplied is too small for it to be a danger to the patient. For example,in one embodiment, the IJV is partially occluded for 3 to 5 seconds.

It is not dangerous to partially occlude the internal jugular vein onone side of the neck. The Quickenstedt maneuver, although now consideredunnecessary due to better imaging modalities like MRI and CAT, was usedby the medical profession for many decades to diagnose spinal stenosis.This maneuver involves fully occluding both internal jugular veins for10-12 seconds. See haps://en.wikipedia.org/wiki/Queckenstedt's_maneuver.

In certain embodiments, after repeating the determination of the ICRSparameter one or more times, for example length of time (T) or ICRScapacity, in certain embodiments, the computer system 50 makes aprediction as to whether clinical deterioration of the patient willoccur. In certain embodiments, after repeating the determination of theICRS parameter, for example length of time (T) or ICRS capacity, incertain embodiments, the computer system 50 makes a prediction as towhether the patient will experience elevated ICP. In each case(prediction of clinical deterioration and/or prediction of elevated ICP)the prediction may include a level of certainty and/or a time by whichthe prediction is expected to occur. The level of certainty may beexpressed in terms of probability or any other suitable format known inthe art. Further, in some cases, the prediction only occurs aftermultiple instances of the determination of the ICRS parameter beingrepeated, or only after a predefined length of time elapses during whichthe potential prediction is repeated, wherein a “potential prediction”refers to an output of a prediction by computer system 50 that is notformalized into an official diagnostic prediction until a predefinedlength of time elapses during which the potential prediction isrepeated.

Accordingly, in some embodiments, the computer system 50 is configuredto predict for the mammalian subject, for example a human patient, atleast one of (i) an elevated ICP of the subject and (ii) clinicaldeterioration of the subject, the prediction being derived from the ICRSparameter, wherein the ICRS parameter is at least one of (i) the lengthof time (T) and (ii) the intracranial reserve space (ICRS) capacity.

V is the volume velocity, V, (linear velocity times cross-section ofIJV) of the blood outflow blocked at the IJV divided by the pressure, P,in mm Hg applied at the IJV, and T is the time from the partialocclusion until the ICP waveform is compressed at a predefined amount,such as when the amplitude of the ICP waveform declines a predefinedamount such as 90%. C is the percentage of the cross-section of the IJVthat was occluded. The units of the ICRS parameter are therefore cm³ (orother distance units cubed) per mm Hg (i.e. volume per pressure). Thisprovides a measure of the blood outflow blocked and caused to accumulatein the cranium for a given pressure in mm Hg applied to the IJV during agiven length of time.

In some embodiments, and because what constitutes a normal ICRS varieswith the ICP of the individual, the computer system 50 is configured todetermine the ICRS/ICP Pressure rather than the ICRS capacity. The ICPmay be supplied from another source such as a direct invasive source orit may be supplied by the non-invasive system of the present invention.Accordingly, the computer system according to this embodiment isconfigured in some embodiments to determine ICRS/ICP from the volumevelocity of the IJV (linear velocity times cross-section of vein) timesT (duration of time during which partial occlusion occurred) and timesC, the percentage of the cross-section of the IJV that was occluded bythe partial occlusion, for example 0.05 (i.e. 5% occlusion) or 0.10(i.e. 10% occlusion) 0.15 (i.e. (15% occlusion) or another percentagebetween 5% and 15% and divided by pressure (P)=to yield ICRS absolutevolume per units of pressure or cm cubed per mmHg The pressure (P) usedfor this equation is the pressure IJV at a time when the IJV pressure isdeemed to correspond to or be equal to or approximately equal to the ICPpressure, namely (assuming the ICP is not otherwise available from aninvasive source or from another source and is supplied by the presentinvention) when a variability characteristics of the ICP waveform beginsto decrease in variability as measured by amplitude or anothervariability characteristic.

The reason that IJV pressure is assumed to equal ICP at that point isthat, after partial occlusion, once brain tissue pulsations start todecline as evidenced by amplitude or another ICP waveform characteristicthat declines, there is a shortage of space in the areas of the craniumwhere the brain tissue pulsates. This means that the partial occlusionat the IJV has been strong enough to overcome the flow of venous bloodfrom the cranium to the IJV, and the upstream effects in the craniumreflect this. This means blood is not flowing between the cranium andthe IJV which indicates equal pressure at both the IJV and the blood inthe cranium. Applicant is measuring ICP by a method analogous toarterial blood pressure on the arm. In this case, the force of thepartial occlusion is sufficient to decrease ICP wave amplitude (or othervariability parameter) in the brain.

Equation (2): ICRS=V/P·T·C, wherein V is the volume velocity of theblood flowing across the IJV for example just after partial occlusion,wherein P is the pressure at IJJ at a time when such pressurecorresponds to ICP, namely when decline in variability of ICP waveformcommences, wherein T is the length of time from partial occlusion untila predetermined decline in variability of the ICP waveform occurred andwherein “C” is the percentage of the cross-section of the internaljugular vein that has been partially occluded.

P as used in the above equation (2) can also be thought of as thepressure to IJV necessary for decreasing of venous output and decreasingof ICP waves variability (for example amplitude) to a predefined degreeof compressed state. Likewise, T as used in equation (2) can be thoughtof as the time needed for pressure, P, to IJV to generate this decreaseof ICP wave variability (i.e. brain pulsation effacement). The linearvelocity and cross-section of the IJV or ICA is obtained by the computersystem directly from the ultrasound probe 35A which is at the distal endof the pressure application instrument 30 applied to the subject's neckon the supine position on the level C3 C4 vertebrae. This probe 35Ashould not be confused with the ultrasound probe 20 place on thepatient's skull. In some embodiments, one or more processors of thecomputer system are configured to determine an ICRS parameter from arelationship of ΔV/ΔP, wherein ΔV is the difference in volume velocitybetween two points in time and wherein ΔP is the difference in pressurebetween two points in time.

Accordingly, the computer system 50 of system 10 is configured in someembodiments to send an alert or to display a determination of an ICRSparameter, for example an absolute volume comprising or corresponding tothe ICRS capacity, or a volume divided by a pressure corresponding tothe ICRS per unit pressure. The pressure is the IJV pressure at a timewhen it is understood to equal or approximately equal the ICP pressure,for example at the beginning of decline in variability of the ICPwaveform. This determination of the ICRS parameter is based, in someembodiments, on the volume velocity (V), the percentage of partialocclusion of the IJV, length of time (T) and in appropriate embodimentsthe given IJV pressure applied.

One particular useful output for physicians and other health careprofessionals or assistants from the system 10 of the present inventionis the absolute length of time (T), for example in seconds ormilliseconds, from the partial occlusion of the IJV until thecompression of the waveform variability characteristic (i.e. amplitude,an area under the curve, dominant frequency, direction of high frequencyshift, a phase shift or a multiaxial spectroscopy of the waveform).Another useful output for physicians and other health care professionalsor assistants from the system 10 of the present invention is therelative length of time (T), for example in seconds or milliseconds,from the partial occlusion of the IJV until the compression of thewaveform variability characteristic (i.e. amplitude, an area under thecurve, dominant frequency, direction of high frequency shift, a phaseshift or a multiaxial spectroscopy of the waveform) compared to aprevious measurement, for example a recent measurement using the presentinvention. Another useful output for physicians and other health careprofessionals or assistants from the system 10 of the present inventionis a determination whether the length of time (T) from the partialocclusion of the IJV until the compression of the waveform is within aparticular range of time, or in other embodiments is equal to a specificscalar time quantity, for example a time in seconds or milliseconds thatis considered normal for a person's ICRS to become “occupied” uponcommencement of partial occlusion of the IJV. This “normal” time maydepend on the age of the individual. This “normal” time may depend onother characteristics of the individual, such as normality of ICP leveland age. For example, many, although not all, elderly people experienceatrophy of the brain tissue and this generates a larger space or ICRS.Similarly, elevated ICP is associated with smaller ICRS. Accordingly,one is able to create handy physical charts or digital charts or look-uptables or other data that in some cases is provided to computer system50 that provide the “normal” length of time expected for “occupying” theICRS upon partial occlusion of IJV based on one or more other parameterssuch as age, health including the existence of an intracranial growth, apathology, ICP or another parameter. The “normal” times can be simplemagnitudes or can be ranges of magnitudes, for example 3 to 5 seconds.

In some embodiments, the specific scalar normal time quantity is 2seconds or 3 second or 2.5 seconds or anything between 2 and 3 secondsor another scalar time amount greater than 3 seconds or less than 2seconds. The time represents the “normal” expected amount of time forthe ICRS to become occupied by the blood flow blocked at the IJV for ahealthy person, possibly at a given age. This time would in someembodiments also take into consideration the pressure applied to theIJV, for example the pressure applied at the time the predefined amountof compression of the ICP waveform occurs. When compression is referredto, what is meant here is decline in variability of a waveform parameterto a predefined degree.

As mentioned, the variability of the waveform characteristic, forexample amplitude, is defined for example as a difference between thehighest and lowest amplitude (or other characteristic) during a setcycle of say 10 milliseconds from the partial occlusion—called theinitial variability or the variability at the first cycle. Then thevariability of the ICP waveform during each subsequent time cycle, forexample each subsequent 10 milliseconds, is monitored from when thepartial occlusion of the IJV commenced. Then, when the variability ofthe waveform has reached a predefined percentage lower than the originalvariability, the predefined amount of compression of the waveform hasbeen deemed to have occurred and that represents the end time (the starttime being the commencement of the partial occlusion) for purposes ofmeasuring the length of time (T), one of the ICRS parameters used in thepresent invention.

The IJV is therefore monitored to see when the partial occlusion beginssince the partial occlusion does not commence the instant that pressureis applied to the skin above the IJV by the instrument 30 of system 10,although it typically takes less than a second for partial occlusion tooccur from when such pressure is applied to the skin. This partialocclusion is visually detectable by a user on an image of the IJVderived from the ultrasound probe converted to a display, orautomatically by the software 55 of computer system 50 such as specialpurpose software. In order to achieve the desired degree of partialocclusion, for example between 5% and 15%, or in other non-limitingexamples between 5% and 10%, a small amount of time elapses aftercommencement of pressure on the skin above the IJV. The time ofcommencement of actual partial occlusion of the IJV is determined by thecomputer system that receives ultrasound images of the IJV.

Another particularly useful output provided in some embodiments by thecomputer system 50 is the ICRS capacity as determined from the bloodflow blocked at the IJV. One can create handy charts or digital chartsor look-up tables correlating the “normal” ICRS capacity as determinedby partial occlusion of the IJV based on age and other parameters, suchas health, pathology, ICP or otherwise, to which the actual measurementscan be compared.

From the output of the intracranial reserve space parameter, which maybe the length of time (T) or the ICRS capacity or the ICRS/ICP, the oneor more processors of the computer system are configured in some casesto determine a suspicion that clinical deterioration of the subjecteither occurred or is predicted to occur.

Applicant believes that it is preferable using the systems and methodsof the present invention to partially occlude the internal jugular veinon the right side of the neck rather than on the left side, although thepresent invention may certainly be implemented by partial occlusion ofthe internal jugular vein on the right side or the left side, and insome embodiments partial occlusion is performed on one side and later onthe opposite side. Recent published articles of Igor D. Stulin (ZhNevrol Psikhiatr Im S S Korsakova 2014; 114(5):39-41) observe aphysiological asymmetry of the IJV. Applicant believes based on thesearticles that the ICRS parameters obtained by the present inventionwould be more precise if the partial occlusion is on the right sidesince the right IJV is straighter than the left IJV and thereby entersthe heart more directly. Secondly, Applicant also believes that partialocclusion of the right IJV is safer because of its wider diameteraccording to the asymmetry found by Stulin and others, at least for mostpatients. However, if it is learned by ultrasound or otherwise that fora given patient the asymmetry is such that the left jugular vein iswider in diameter, then in some embodiments the left IJV is used,although in other embodiments the right IJV is used.

When partial occlusion is continued beyond the subsequent time (T) atwhich the waveform is sufficiently compressed so as to exhibit apredefined decline in variability, a normal healthy person would beexpected to experience a cerebral venous blood flow autoregulationmechanism whereby the internal jugular vein located on the opposite sideof the neck from the IJV that was partially occluded, expands indiameter and brain tissue pulsation returns to normal. What happens isthat the venous blood blocked in one hemisphere of the brain fromexiting moves to the other hemisphere of the brain through the superiorsagittal sinus vein (SSS) and exits through venous shunts that havesprouted into bridging veins between the intracranial and extra-cranialareas.

FIG. 10 depicts the amplitude of the ICP waveform from when t=0. Atabout t=1.6 seconds, partial occlusion of the internal jugular vein onone side of the neck is performed. There is an upward shift in basisline after that. At approximately t=3.25 seconds, the predefined declinein variability of the ICP wave amplitude has occurred. Fromapproximately t=3.25 seconds until a normalization time at approximatelyt=6.5 seconds, the partial occlusion is continued and as shown in FIG.10, the cross-filling time during which normalization of the ICP waveamplitude variability is restored occurs. The part of the venous flowautoregulation time (also called cross-filling time) that is after thepredefined decline in variability of the ICP waveform is referred toherein as the “further length of time” to distinguish it from the“length of time (T)” that encompasses the interval running from thepartial occlusion of the IJV until the predefined decline in variabilityof the ICP waveform. In this case, FIG. 10 shows that this “furtherlength of time” for normalization after the predefined decline invariability took about 3.25 seconds.

Accordingly, in some embodiments, the computer system is configured todetermine a “further length of time” beginning from the time at whichthe waveform is sufficiently compressed so as to exhibit the predefineddecline in variability to a normalization time at which the predefineddecline in variability has been reversed (brain tissue pulsation hasbeen restored), the reversal such that a variability of the waveform atthe normalization time equals, within a predefined degree of accuracy, avariability of the waveform at the start time. The normalization timehas occurred when either (i) the amplitude of the ICP waveform returnsto equal what it was at the start of the partial occlusion (i.e. equalto within a predefined level of accuracy) or (ii) the variability of theICP waveform returns to be equal to what it was at the start of thepartial occlusion, within a predefined level of accuracy. Note that thevariability of the ICP waveform is measured using any of the sameparameters used to measure the variability of the ICP waveform whendetermining the predefined decline in variability. The “further lengthof time” is defined as the time interval from the “subsequent time (T)at which the waveform is sufficiently compressed so as to exhibit apredefined decline in variability” until the “normalization time”. Theterm “subsequent time” was used simply because it was subsequent to thestart time of the partial occlusion and was used as the endpoint of thelength of time used to measure the ICRS parameter. In some embodiments,the predefined level of accuracy is to within 5% and in otherembodiments the predefined level of accuracy is to within 1% or 3% or 7%or 10% or 15% or 20% or 30% or 50% or a different percentage between 1%and 50%.

Accordingly, in some embodiments, the computer system 50 is configuredto send an alert predicting future clinical deterioration of the subjectif the further length of time is excessive or too short relative anexpected normal further length of time. The expected “further length oftime” for healthy individuals may vary depending on a number of factorsbut on average for adults it is approximately two to four seconds andabout three seconds. In addition, the expected normal “further length oftime” for normalization is in some embodiments determined based on whatis expected normal for that particular patient from prior investigationof that patient rather than by comparing the particular patient to thepopulation based on age or other factors.

Accordingly, in cases in which the ICRS parameter is found to be normalwhen checking a specific patient with the present invention, if the“further length of time” to reach normalization, i.e. to restore braintissue pulsation, is excessive or too short, the system 10 of thepresent invention is configured in certain embodiments to send an alert.This alert in some embodiments predicts clinical deterioration of thepatient. Since occupation of the ICRS has not yet occurred, thepredicted future clinical deterioration is not immediate clinicaldeterioration but rather is more distant than “immediate, for example aday or two in the future. Thus, this further length of time is an evenearlier predictor or marker for future clinical deterioration of apatient than the length of time until the ICRS is occupied.

In some embodiments, system 10 or it components (probe 20, instrument 30including second probe 35A, computer system 50) is utilized inaccordance with any of the steps or actions described below in relationto method 100.

In one embodiment, the present invention is a system for non-invasivemonitoring of an intracranial reserve space (ICRS) parameter of amammalian subject, comprising: a multi-frequency ultrasound probeconfigured, beginning at a start time, to emit and receive ultrasoundwaves into and from a head of the subject and to produce a signal ofbrain tissue pulsation; an instrument configured to non-invasively applya pressure to effectuate a partial occlusion of the cross-section of aninternal jugular vein of the subject, the partial occlusion starting atthe start time, the instrument including a second ultrasound probeconfigured to produce a second signal for imaging a cross-section of theinternal jugular vein, the second ultrasound probe having a Dopplerultrasound output for measuring a linear velocity of venous blood at theinternal jugular vein; and a computer system configured to receive thesignal and an output of the start time of the partial occlusion of theinternal jugular vein of the subject. The computer system 50 is alsoconfigured to receive the second signal and to derive from the secondsignal an image of the internal jugular vein, for example thecross-section of the IJV and to determine the linear velocity of venousblood at the IJV.

The computer system is also configured, using one or more processors, toderive from the signal an intracranial brain tissue pulsation waveform,and to determine an ICRS capacity from (i) a length of time (T) from thestart time to a subsequent time at which the waveform is sufficientlycompressed so as to exhibit a predefined decline in variability and from(ii) a volume velocity (V) of blocked venous blood output occluded atthe IJV, wherein the volume velocity is determined by the computersystem from the linear velocity of the internal jugular vein derivedfrom the Doppler ultrasound output and from the image(s) of thecross-section of the internal jugular vein.

The present invention, in one embodiment, is a method 100 ofnon-invasively monitoring an intra-cranial reserve space parameter of amammalian subject. Method 100 comprises a step 110 of using a probe toemit and receive ultrasound frequency waves into and from a body part,for example a head, of the subject during a time interval and to producea signal corresponding to pulsation of brain tissue of the subject. Theprobe, in one embodiment, is a two-dimensional probe with a loweremitter frequency than the receiver frequency. For example, the emittermay emit at 0.5-3 MHZ while the receiver receives at approximately 1.0MHz-6 MHz, which provides a high resolution scan. In some embodiments,the probe 20 has any of the characteristics mentioned in regard to probe20 of system 10.

Method 100 comprises a step 120, in one embodiment, of applying aninstrument 30 such as instrument 30 of system 10 to a neck of thesubject to non-invasively partially occlude an internal jugular vein ofthe subject, the partial occlusion starting at a start time of the timeinterval. In some embodiments of method 100 the instrument 30 has any ofthe characteristics described in relation to instrument 30 of system 10.An example of the instrument 30 is a device such as shown in FIG. 6 andFIG. 8 comprising for example a step-wise motor, syringe for housing atleast one piston and a fluid pump for a fluid such as air. Theinstrument 30 applies the pressure by applying an initial pressure andthen increasing the pressure from the initial pressure stepwise inuniform increments until the predefined decline in variability occurs.The instrument 30, in one particular embodiment, also has attached toit, for example at the other end away from the subject, a manometer formeasuring the IJV pressure.

The measured internal jugular venous pressure (IJVP) by manometer 39 ofinstrument 30 is substantially equal to the subject's ICP at a momentthat the amplitude (or other ICP wave variability parameter) of the ICPwaves starts to decline. The reason for this is that at that point thepressure of the blood in the cranium is substantially equal to thepressure against the blood in the cranium.

Accordingly, in one embodiment step 120 comprises: using an instrument,non-invasively applying a pressure to a neck of the subject toeffectuate a partial occlusion of an internal jugular vein of thesubject, the partial occlusion starting at a start time of the timeinterval, the instrument measuring the pressure and including a distalultrasound probe configured for producing a second signal for imagingthe internal jugular vein, for example for imaging a cross-section ofthe internal jugular vein or another view of the internal jugular veinthat allows monitoring of the cross-section or diameter of the internaljugular vein (or allows monitoring some other parameter of the IJVsufficient to reveal when the partial occlusion has started).

Method 100 has a step 130, in one embodiment, of receiving, by means ofa computer system, the signal from the ultrasound probe 20 (i.e. theprobe applied to the subject's head) and deriving from this signal anintracranial brain tissue pulsation waveform of the tissue pulsation ofthe subject, for example in the cranium of the subject. In certainembodiments, the computer system is also configured to receive an outputof the start time of the interval from when partial occlusion of theinternal jugular vein commenced.

In some embodiments, step 130 also comprises the computer systemreceiving the second signal and deriving from the second signal imagesof the internal jugular vein, for example its cross-section, and in somecases determining the extent of the partial occlusion (for example thepartial cross-sectional occlusion) of the IJV.

In certain embodiments of method 100, there is a further step 140 ofdetermining, by means of one or more processors of the computer system,a length of time (T) from the start time of the interval (when thepartial occlusion commenced) to a time when the ICP waveformsubstantially straightens, that is when the waveform is sufficientlycompressed so as to exhibit a predefined decline in variability. Thevariability of the waveform comprises at least one of the followingparameters: (i) a variability of an amplitude of the waveform and (ii) avariability of an area under the curve of the waveform, (iii) avariability of a dominant frequency of the waveform, (iv) a direction ofhigh frequency shift of the waveform, (v) a phase shift of the waveformand (vi) a variability of a multiaxial spectroscopy of the waveform. Inanother embodiment, variability of the intracranial brain tissuepulsation waveform comprises a variability of at least one of thefollowing ICP waveform parameters: (i) an amplitude of the waveform and(ii) an area under the curve of the waveform, (iii) a dominant frequencyof the waveform (for example a frequency between 0.1 and 35 MHz) and(iv) and (vi) a multiaxial spectroscopy of the waveform (ICPWMS). Thespectroscopy referred to herein is a mechanical motion (pulsatility)spectroscopy, not a magnetic or electrical spectroscopy. Other functionsthat indicate variability of the ICP waveform are also within the methodof the present invention, including but not necessarily limited tocombinations and/or derivatives of the above six examples of ICPwaveform variability indicia/parameters.

Steps 110, 120, 130 and 140 of method 100 in some embodiments arerepeated dynamically at least once (for example after an interval ofminutes or hours or a day or days). The results of the two or moremeasurements of the ICRS parameter are compared to determine if therehas been a change in length of time (T) or a change in the ICRScapacity.

In some embodiments, there is a step of determining by means of one ormore processors of the computer system 50, the ICRS capacity based onthe volume velocity (V) multiplied by time (T) and multiplied by thepercentage of the IJV that has been partial occluded. In still otherembodiments, there is step of determining the ICRS (i.e. the ICRScapacity) divided by the intracranial pressure.

In some embodiments, there is step of converting the signal from theultrasound probe applied of the head of the subject into a dynamic imageof a pulsatility of brain tissue, wherein the image is of the sector ofthe head that the multi-frequency ultrasound probe received ultrasoundwaves from.

In some embodiments, there is a step of providing an output, to thephysician or other user, of the ICRS parameter, for example the ICRScapacity, the length of time (T), and/or the ICRS capacity divided byintracranial pressure of the subject or another useful parameter and toprovide such output dynamically and/or repeatedly, such as every minuteor every 5 or 10 or 20 or 30 or 40 or 50 minutes or every hours or everyseveral hours or every 3 or 4 or 5 or 6 or 9 or 12 hours or every day orevery 2 or 3 or 3 or 4 or 5 or 7 or 10 days or every two weeks or everymonth. The computer system in some embodiments also determines that thesubject has an abnormal intracranial reserve space and/or that clinicaldeterioration is either predicted to occur or inferred to have occurred.

Method 100 results in a length of time (T₁) having been determined. Insome embodiments, method 100 is repeated and a further or subsequentlength of time (T₂) is determined In some embodiments, the method 100 isrepeated and predicts at least one of (i) elevated ICP and (ii) clinicaldeterioration of the patient, if the subsequent length of time (T₂) isless than the length of time (T₁) by a predefined amount (the term“amount” including both absolute amounts and relative amounts). Thepredefined amount can be a percentage or an absolute amount suitablydetermined based on age, medical condition and any other suitablefactor. For example the predefined amount in some embodiments is aone-third decline or a 40% decline in the length of time, or 50%, or60%, or 70%, or 80%, or 90%, or 100%, or a greater or lower percentagedecline or some other numerical percentage between one-third and 100%,or a decline of at least a predefined absolute amount such as at leastone half a second, at least three-quarters of a second, at least onesecond, at least 1.5 seconds at least 2 seconds, at least 2.5 seconds,at least 3 seconds or at least 3.5 or at least 4 seconds or any numberin between 1 second and 4 second or greater than 4 seconds.

The method 100, or a variation thereof in which the ICRS parameter isthe ICRS capacity rather than the length of time (T), may be performedand then repeated within a relative short interval dynamically with theresults compared to determine if there has been a sudden or recentoccupying of the ICRS.

The method 100 of the present invention in some embodiments has any ofthe characteristics described in relation to system 10. For example, insome embodiments of method 100, the multi-frequency ultrasound probe 20is configured to receive ultrasound waves from at least two differentintracranial locations, as discussed in relation to system 10. Inanother example, in some embodiments, method 100 comprises sending analert predicting at least one of (i) an elevated intracranial pressureand (ii) clinical deterioration of the subject, wherein the computersystem may be configured to send the alert based on the length of time(T), the ICRS capacity and/or a given intracranial pressure applied.

The following is an example of an experimental use of one aspect of theclaimed invention. An elderly human subject is admitted for treatment toa hospital, reporting a fall. The intracranial reserve space of thesubject was measured. The computer system 50 outputs that it took 8seconds for the ICRS of the subject to be occupied, which indicates highgrade brain atrophy. A CT was run and it revealed mild subarachnoid andmild intraparenchymal hemorrhage right parietal. This does not justifysurgery. During observation, the intracranial reserve space wasre-measured about three hours after the first CT. The ICRS takes only 4seconds to become occupied according to the second measurement. Thisindicates a growth of the volume of the hemorrhage, or brain swelling. Asecond CT was run even though only three hours had elapsed from thefirst CT, which is not the norm at least according to the guidelines ofthe American Academy of Neurology, since 6 hours had not elapsed. Theinformation from the second ICRS measurement indicated the need for thesecond CT. The second CT revealed a large hemorrhage. Surgery wasperformed, including a right parietal craniotomoy and removal of theintracranial hemorrhage.

While the invention has been described with respect to a limited numberof embodiments, it will be appreciated that many variations,modifications and other applications of the invention may be made.Therefore, the claimed invention as recited in the claims that follow isnot limited to the embodiments described herein.

What is claimed is:
 1. A system for non-invasive monitoring of anintracranial reserve space (ICRS) parameter of a mammalian subject,comprising: a multi-frequency at least two-dimensional ultrasound probeconfigured, beginning at a start time, to emit and receive ultrasoundwaves into and from a head of the subject and to produce a signal ofintracranial brain tissue pulsations in at least a horizontal spatialand a vertical spatial dimension, the brain tissue pulsations responsiveto pulses of a heart systole and/or arterial pressure; an instrumentconfigured to non-invasively apply a pressure to effectuate a partialocclusion of an internal jugular vein of the subject, the partialocclusion starting at the start time, the instrument including a secondultrasound probe configured to produce a second signal for imaging theinternal jugular vein; and a computer system configured to receive thesignal and an output of the start time of the partial occlusion of theinternal jugular vein of the subject, the computer system alsoconfigured, using one or more processors, to derive from the signal ofintracranial brain tissue pulsations an intracranial brain tissuepulsation waveform based on at least three-dimensional pulsatility ofthe intracranial brain tissue, and to determine a length of time fromthe start time to a subsequent time at which the waveform issufficiently compressed so as to exhibit a predefined decline invariability of at least 10%, the computer system also configured toreceive the second signal and to derive from the second signal images ofthe internal jugular vein.
 2. The system of claim 1, wherein themulti-frequency ultrasound probe emits in transmission mode at anemitter frequency and the probe receives at a receiver frequency suchthat the emitter frequency is lower than the receiver frequency.
 3. Thesystem of claim 1, wherein the instrument is configured to measure thepressure and wherein the instrument is configured to apply an initialpressure and subsequent greater pressures in uniform increments to theinternal jugular vein.
 4. The system of claim 1, wherein the instrumentincludes a motor or a compressor, at least one piston movable within ahousing, and an applicator that includes the second ultrasound probe, adistal end of the applicator shaped to engage the neck of the subject.5. The system of claim 1, wherein the multi-frequency ultrasound probehas a piezoelectric array configured to adapt to a shape of the skull.6. The system of claim 1, wherein the multi-frequency ultrasound probeemits at a frequency of 0.5 to 3 MHz and receives at a frequency of 1.0MHz to 6.0 MHz.
 7. The system of claim 1, wherein an end of themulti-frequency ultrasound probe is shaped to conform to a skull andwherein the ultrasound probe emits at a frequency of about 1.0 MHz andreceives at a frequency of up to 1.76 MHz using a carrier frequency ofabout 0.5 MHz to 1.76 MHz.
 8. The system of claim 1, wherein variabilityof the waveform comprises at least one of the following parameters: (i)a variability of an amplitude of the waveform and (ii) a variability ofan area under the curve of the waveform, (iii) a variability of adominant frequency of the waveform (iv) a direction of high frequencyshift of the waveform, (v) a phase shift of the waveform and (vi) avariability of a multiaxial spectroscopy of the waveform.
 9. The systemof claim 1, wherein the computer system is further configured to convertthe signal into a dynamic image of a multiaxial pulsatility of braintissue in at least a part of the head that the probe received ultrasoundwaves from.
 10. The system of claim 1, wherein the computer system isconfigured to determine a suspicion that clinical deterioration of thesubject is predicted to occur.
 11. The system of claim 1, wherein thecomputer system is configured to predict at least one of (i) an elevatedICP of the subject and (ii) clinical deterioration of the subject, theprediction being derived from the determination of an intracranialreserve space (ICRS) parameter, wherein the ICRS parameter is at leastone of (i) the length of time (T) and (ii) the intracranial reservespace (ICRS) capacity.
 12. The system of claim 1, wherein the computersystem is further configured to determine a magnitude of an intracranialreserve space (ICRS) parameter during the length of time (T).
 13. Thesystem of claim 1, wherein the computer system is configured todetermine a magnitude of an ICRS capacity based on a volume velocity (V)of blocked venous blood output occluded at the IJV multiplied by thelength of time (T).
 14. The system of claim 1, wherein the computersystem is configured to send an alert predicting at least one of (i) anelevated intracranial pressure and (ii) clinical deterioration of thesubject.
 15. The system of claim 1, wherein the computer system isconfigured to send an alert based on at least one of the length of time(T) and an intracranial reserve space capacity.
 16. The system of claim15, wherein the alert determines if the length of time is within a rangeof two to three seconds for a given pressure.
 17. The system of claim 1,wherein the multi-frequency ultrasound probe is configured to receiveultrasound waves from at least two different intracranial locations. 18.The system of claim 17, wherein the two different intracranial locationsare dissimilar according to predetermined criteria.
 19. The system ofclaim 17, wherein the computer system is configured to determine arepresentative ICRS parameter from separate respective ICRS magnitudesat the at least two different intracranial locations.
 20. The system ofclaim 1, wherein one or more processors of the computer system areconfigured to determine an ICRS parameter from a relationship of ΔV/ΔP.21. The system of claim 1, wherein one or more processors of thecomputer system are configured to determine a suspicion that clinicaldeterioration either occurred or is predicted.
 22. The system of claim1, wherein the intracranial brain tissue pulsation waveform is providedby the computer system at a resolution of at least 6000 points percycle.
 23. The system of claim 1, wherein the computer system is alsoconfigured to derive a cross-sectional image of the IJV from the secondsignal and to determine an extent of partial occlusion of the IJV. 24.The system of claim 1, wherein the multi-frequency ultrasound probe isconfigured to operate in both a transmission mode and an impulse modesuch that one of the (i) emitter and (ii) receiver operates intransmission mode and another of the (i) emitter and (ii) receiveroperates in impulse mode.
 25. The system of claim 1, wherein thecomputer system is configured to determine a further length of timebeginning from the time at which the waveform is sufficiently compressedso as to exhibit the predefined decline in variability to anormalization time at which the predefined decline in variability hasbeen reversed, the reversal such that a variability of the waveform atthe normalization time equals, within a predefined degree of accuracy, avariability of the waveform at the start time.
 26. The system of claim25, wherein the computer system is configured to send an alertpredicting future clinical deterioration of the subject if the furtherlength of time is excessive or too short relative an expected normalfurther length of time.
 27. The system of claim 1, further comprising adisplay forming part of or connected to the computer system, the displayconfigured to dynamically display the intracranial pressure waveform soas to visually depict the variability of said waveform.
 28. The systemof claim 1, wherein the multi-frequency ultrasound probe, the secondultrasound probe and the one or more processors work synchronously. 29.A method of non-invasively monitoring an intracranial reserve space(ICRS) parameter of a mammalian subject, comprising: using an at leasttwo-dimensional multi-frequency ultrasound probe, emitting and receivingultrasound waves into and from a head of a subject so as to produce asignal of intracranial brain tissue pulsations of the subject during atime interval in at least a horizontal spatial and a vertical spatialdimension, the brain tissue pulsations responsive to pulses of a heartsystole and/or arterial pressure; using an instrument, non-invasivelyapplying a pressure to a neck of the subject to effectuate a partialocclusion of an internal jugular vein of the subject, the partialocclusion starting at a start time of the time interval, the instrumentmeasuring the pressure and including a distal ultrasound probeconfigured to produce a second signal for imaging the internal jugularvein; using a computer system to receive the signal and derive from thesignal an intracranial brain tissue pulsation waveform of the subjectand the volume velocity of the internal jugular vein, the computersystem also configured to receive an output of the start time and tomonitor time from the start time, the computer system also configured toreceive the second signal and to derive from the second signal images ofthe internal jugular vein; and determining, using one or more processorsof the computer system, a length of time (T) from the start time to atime when the intracranial brain tissue pulsation waveform issufficiently compressed so as to exhibit a predefined decline invariability of at least 10%.
 30. The method of claim 29, furthercomprising the multi-frequency ultrasound probe emitting in transmissionmode at an emitter frequency and the probe receiving at a receiverfrequency such that the emitter frequency is lower than the receiverfrequency.
 31. The method of claim 29, wherein the variability of thewaveform comprises at least one of the following parameters: (i) avariability of an amplitude of the waveform, (ii) a variability of anarea under the curve of the waveform, (iii) a variability of a dominantfrequency of the waveform (iv) a direction of high frequency shift ofthe waveform, (v) a phase shift of the waveform and (vi) a variabilityof a multiaxial spectroscopy of the waveform.
 32. The method of claim29, further comprising converting the signal into a dynamic image of amultiaxial pulsatility of brain tissue in a sector of the head fromwhich the multi-frequency ultrasound probe received ultrasound waves.33. The method of claim 29, further comprising having themulti-frequency ultrasound probe emits at between 0.5 and 1.1 MHz andreceives at between 1.0 and 2.2 MHz using a carrier frequency of 0.5 to2.2 MHz.
 34. The method of claim 29, further comprising applying thepressure by applying an initial pressure and then increasing thepressure from the initial pressure stepwise in uniform increments untilthe predefined decline in variability of the ICP waveform occurs. 35.The method of claim 29, further comprising determining that the subjecthas an abnormal intracranial reserve space and that clinicaldeterioration is either predicted to occur or inferred to have occurred.36. The method of claim 29, further comprising determining, using theone or more processors, a magnitude or a relative magnitude of anintracranial reserve space (ICRS) parameter given the pressure appliedfor the length of time (T).
 37. The method of claim 36, furthercomprising determining the magnitude of the ICRS parameter using arelationship of a volume velocity (V) of venous blood output occluded atthe internal jugular vein for a given pressure (P) taking intoconsideration the length of time (T) of application of the pressure, andwherein the ultrasound Doppler outputs the linear velocity andcross-sectional diameter of the internal jugular vein.
 38. The method ofclaim 29, further comprising determining that a further medical actionis needed if the length of time (T) is less than a predefined length oftime for a given pressure applied to the subject to effectuate thepartial occlusion, wherein the predefined length of time has a specificlength that is at least 2 seconds and not more than 3 seconds.
 39. Themethod of claim 29, further comprising determining an intracranialpressure from the pressure applied to the subject at a time when theintracranial brain tissue pulsation waveform begins to decline invariability.
 40. The method of claim 29, further comprising monitoringthe ICRS parameter dynamically.
 41. The method of claim 29, furthercomprising applying the pressure to the internal jugular vein forbetween 3 and 25 seconds so as to partially occlude 5% to 25% of across-section of the internal jugular vein.
 42. The method of claim 29,further comprising applying the pressure to the internal jugular veinfor between 3 and 10 seconds so as to partially occlude 5% to 15% of across-section of the internal jugular vein.
 43. The method of claim 29,further comprising repeating the method at least once so as to determinea subsequent length of time (T), and predicting at least one of elevatedICP and clinical deterioration, if the subsequent length of time (T) isless than the length of time (T) by a predefined amount.
 44. A systemfor non-invasive monitoring of an intracranial reserve space (ICRS)parameter of a mammalian subject, comprising: a multi-frequencyultrasound probe configured, beginning at a start time, to emit andreceive ultrasound waves into and from a head of the subject and toproduce a signal of brain tissue pulsation; an instrument configured tonon-invasively apply a pressure to effectuate a partial occlusion of across-section of an internal jugular vein of the subject, the partialocclusion starting at the start time, the instrument including a secondultrasound probe configured to produce a second signal for imaging across-section of the internal jugular vein, the second ultrasound probehaving a Doppler ultrasound output for measuring a linear velocity ofvenous blood at the internal jugular vein; and a computer systemconfigured to receive the signal and an output of the start time of thepartial occlusion of the internal jugular vein of the subject, thecomputer system also configured to receive the second signal and toderive from the second signal an image of the cross-section of theinternal jugular vein and to determine the linear velocity of venousblood at the internal jugular vein, the computer system also configured,using one or more processors, to derive from the signal an intracranialbrain tissue pulsation waveform, and to determine an ICRS capacity from(i) a length of time (T) from the start time to a subsequent time atwhich the waveform is sufficiently compressed so as to exhibit apredefined decline in variability of at least 10% and from (ii) a volumevelocity (V) of blocked venous blood output occluded at the IJV, whereinthe volume velocity is determined by the computer system from the linearvelocity of the internal jugular vein derived from the Dopplerultrasound output and from the image of the cross-section of theinternal jugular vein.